Dihydroindole and tetrahydroquinoline derivatives

ABSTRACT

The present invention relates to novel dihydroindole and tetrahydroquinoline derivatives and pharmaceutically acceptable salts and/or pharmaceutically acceptable esters thereof. The compounds are useful for the treatment and/or prophylaxis of diseases which are associated with 2,3-oxidosqualene-lanosterol cyclase such as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycoses, gallstones, tumors and/or hyperproliferative disorders, and treatment and/or prophylaxis of impaired glucose tolerance and diabetes.

PRIORITY TO RELATED APPLICATIONS

This application is a Division of Ser. No. 10/014,959, filed Dec. 11,2001, which is now U.S. Pat. No. 6,706,751.

FIELD OF THE INVENTION

The present invention is concerned with novel dihydroindoleand-tetrahydroquinoline derivatives, their manufacture and their use asmedicaments.

BACKGROUND OF THE INVENTION

2,3-oxidosqualene-lanosterol cyclase (EC 5.4.99.) is required for thebiosynthesis of cholesterol, ergosterol and other sterols. Causal riskfactors that directly promote the development of coronary and peripheralatherosclerosis include elevated low-density lipoprotein cholesterol(LDL-C), low high-density lipoprotein cholesterol (HDL-C), hypertension,cigarette smoking and diabetes mellitus. Other synergistic risk factorsinclude elevated concentrations of triglyceride (TG)-rich lipoproteins,small, dense low-density lipoprotein particles, lipoprotein (a) (Lp(a)),and homocysteine. Predisposing risk factors modify the causal orconditional risk factors and thus affect atherogenesis indirectly. Thepredisposing risk factors are obesity, physical inactivity, familyhistory of premature CVD, and male sex. The strong connection betweencoronary heart disease (CHD) and high LDL-C levels in plasma, and thetherapeutic advantage of lowering elevated LDL-C levels are now wellestablished (Gotto et al., Circulation 81, 1990, 1721–1733; Stein etal., Nutr. Metab. Cardiovasc. Dis. 2, 1992, 113–156; Illingworth, Med.Clin. North. Am. 84, 2000, 23–42). Cholesterol-rich, sometimes unstable,atherosclerotic plaques lead to the occlusion of blood vessels resultingin an ischemia or an infarct. Studies with respect to primaryprophylaxis have shown that a lowering of plasma LDL-C levels in plasmareduces the frequency of non-fatal incidences of CHD, while the overallmorbidity remains unchanged. The lowering of plasma LDL-C levels inpatients with pre-established CHD (secondary intervention) reduces CHDmortality and morbidity; meta-analysis of different studies shows thatthis decrease is proportional to the reduction of the LDL-C (Ross etal., Arch. Intern. Med. 159,1999,1793–1802).

The clinical advantage of cholesterol lowering is greater for patientswith pre-established CHD than for asymptomatic persons withhypercholesterolemia. According to current guidelines, cholesterollowering treatment is recommended for patients who had survived amyocardial infarct or patients suffering from angina pectoris or anotheratherosclerotic disease, with a target LDL-C level of 100 mg/dl.

Preparations such as bile acid sequestrants, fibrates, nicotinic acid,probucol as well as statins, i.e. HMG-Co-A reductase inhibitors such assimvastatin and atorvastatin, are used for usual standard therapies. Thebest statins reduce plasma LDL-C effectively by at least 40%, and alsoplasma triglycerides, a synergistic risk factor, but less effectively.In contrast, fibrates reduce plasma triglycerides effectively, but notLDL-C. Combination of a statin and a fibrate proved to be veryefficacious in lowering LDL-C and triglycerides (Ellen and McPherson, J.Cardiol. 81, 1998, 60B–65B), but safety of such a combination remains anissue (Shepherd, Eur. Heart J. 16, 1995, 5–13). A single drug with amixed profile combining effective lowering of both LDL-C andtriglycerides would provide additional clinical benefit to asymptomaticand symptomatic patients.

In humans, statins are well tolerated at standard dosage, but reductionsin non-sterol intermediates in the cholesterol synthesis pathway, suchas isoprenoids and coenzyme Q, may be associated with adverse clinicalevents at high doses (Davignon et al., Can. J. Cardiol. 8, 1992,843–864; Pederson and Tobert, Drug Safety 14, 1996, 11–24).

This has stimulated the search for, and development of compounds thatinhibit cholesterol biosynthesis, yet act distal to the synthesis ofthese important, non-sterol intermediates. 2,3-oxidosqualene:lanosterolcyclase (OSC), a microsomal enzyme, represents a unique target for acholesterol-lowering drug (Morand et al., J. Lipid Res., 38, 1997,373–390; Mark et al., J. Lipid Res. 37, 1996, 148–158). OSC isdownstream of farnesyl-pyrophosphate, beyond the synthesis ofisoprenoids and coenzyme Q. In hamsters, pharmacologically active dosesof an OSC inhibitor showed no adverse side-effects, in contrast to astatin which reduced food-intake and body weight, and increased plasmabilirubin, liver weight and liver triglyceride content (Morand et al.,J. Lipid Res., 38, 1997, 373–390). The compounds described in EuropeanPatent Application No. 636 367, which inhibit OSC and which lower thetotal cholesterol in plasma, belong to these substances.

OSC inhibition does not trigger the overexpression of HMGR because of anindirect, negative feed-back regulatory mechanism involving theproduction of 24(S),25-epoxycholesterol (Peffley et al., Biochem.Pharmacol. 56, 1998, 439–449; Nelson et al., J. Biol. Chem. 256, 1981,1067–1068; Spencer et al., J. Biol. Chem. 260, 1985, 13391–13394; Paniniet al., J. Lipid Res. 27, 1986, 1190–1204; Ness et al., Arch. Biochem.Biophys. 308, 1994, 420–425). This negative feed-back regulatorymechanism is fundamental to the concept of OSC inhibition because (i) itpotentiates synergistically the primary inhibitory effect with anindirect down-regulation of HMGR, and (ii) it prevents the massiveaccumulation of the precursor monooxidosqualene in the liver. Inaddition, 24(S),25-epoxycholesterol was found to be one of the mostpotent agonists of the nuclear receptor LXR (Janowski et al., Proc.Natl. Acad. Sci. USA, 96, 1999, 266–271). Considering that24(S),25-epoxycholesterol is a by-product of inhibition of OSC it ishypothesized that the OSC inhibitors of the present invention could alsoindirectly activate LXR-dependent pathways such as (i)cholesterol-7alpha-hydroxylase to increase the consumption ofcholesterol via the bile acid route, (ii) expression of ABC proteinswith the potential to stimulate reverse cholesterol transport andincrease plasma HDL-C levels (Venkateswaran et al., J. Biol. Chem. 275,2000, 14700–14707; Costet et al., J. Biol. Chem. June 2000, in press;Ordovas, Nutr Rev 58, 2000, 76–79, Schmitz and Kaminsky, Front Biosci 6,2001, D505–D514), and/or inhibit intestinal cholesterol absorption(Mangelsdorf, XIIth International Symposium on Atherosclerosis,Stockholm, June 2000). In addition, possible cross talks between fattyacid and cholesterol metabolism mediated by liver LXR have beenhypothesized (Tobin et al., Mol. Endocrinol. 14, 2000, 741–752).

SUMMARY OF THE INVENTION

The invention relates to compounds of the formula (I)

wherein

-   U is O or a lone pair,-   V is a) O, S, NR¹, or CH₂, and L is lower-alkylene or    lower-alkenylene, b) —CH═CH— or —C≡C—, and L is lower-alkylene or a    single bond,-   W is CO, COO, CONR², CSO, CSNR², SO₂, or SO₂NR²,-   X is hydrogen or one or more optional halogen and/or lower-alkyl    substituents,-   m is 1 or 2,-   n is 0 to 7,-   A¹ is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted    by hydroxy, lower-alkoxy, or thio-lower-alkoxy,-   A² is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,    lower-alkinyl, or lower-alkyl optionally substituted by hydroxy,    lower-alkoxy or thio-lower-alkoxy,-   A³ and A⁴ independently from each other are hydrogen or lower-alkyl,    or-   A¹ and A² or A¹ and A³ are bonded to each other to form a ring and    -A¹-A²- or -A¹-A³- are lower-alkylene or lower-alkenylene,    optionally substituted by R³, in which one —CH₂— group of -A¹-A²- or    -A¹-A³- can optionally be replaced by NR⁴, S, or O,-   A⁵ is cycloalkyl, cycloalkyl-lower-alkyl,    heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl,    heteroaryl-lower-alkyl, lower-alkyl optionally substituted with    hydroxy or lower-alkoxy, alkenyl optionally substituted with    hydroxy, or alkadienyl optionally substituted with hydroxy,-   R³ is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R⁵,R⁶), or    lower-alkyl optionally substituted by hydroxy,-   R¹, R², R⁴, R⁵, and R⁶ independently from each other are hydrogen or    lower-alkyl, and pharmaceutically acceptable salts and/or    pharmaceutically acceptable esters thereof.

The compounds of formula I inhibit OSC and therefore also inhibit thebiosynthesis of cholesterol, ergosterol and other sterols, and reducethe plasma cholesterol levels. They can therefore be used in the therapyand prophylaxis of hypercholesterolemia, hyperlipemia, arteriosclerosisand vascular diseases in general. Furthermore, they can be used in thetherapy and/or prevention of mycoses, parasite infections, gallstones,cholestatic liver disorders, tumors and hyperproliferative disorders,e.g. hyperproliferative skin and vascular disorders. In addition, it hasunexpectedly been found that the compounds of the present invention canalso be of therapeutical use to improve glucose tolerance in order totreat and/or prevent related diseases such as diabetes. The compounds ofthe present invention further exhibit improved pharmacologicalproperties compared to known compounds.

DETAILED DESCRIPTION OF THE INVENTION

Unless otherwise indicated the following definitions are set forth toillustrate and define the meaning and scope of the various terms used todescribe the invention herein.

In this specification the term “lower” is used to mean a groupconsisting of one to seven, preferably of one to four carbon atom(s).

The term “lone pair” refers to an unbound electron pair, in particularto the unbound electron pair of a nitrogen atom in e.g. an amine.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “protecting group” refers to groups such as acyl, azoyl,alkoxycarbonyl, aryloxycarbonyl, or silyl. Examples are e.g.t-butyloxycarbonyl, benzyloxycarbonyl or fluorenylmethyloxycarbonylwhich can be used for the protection of amino groups or trimethylsilyl,dimethyl-tert.-butyl-silyl or tert.-butyl-diphenyl-silyl, which can beused for the protection of hydroxy groups, trityl or p-methoxybenzyl forsulfur, methyl or benzyl for the protection of phenole derivatives,methyl, ethyl or tert.-butyl for the protection of thiophenolederivatives.

The term “alkyl”, alone or in combination with other groups, refers to abranched or straight-chain monovalent saturated aliphatic hydrocarbonradical of one to twenty carbon atoms, preferably one to sixteen carbonatoms, more preferably one to ten carbon atoms. Lower-alkyl groups asdescribed below also are preferred alkyl groups. Alkyl groups can besubstituted e.g. with halogen, hydroxy, lower-alkoxy, thio-lower-alkoxy,lower-alkoxy-carbonyl, NH₂, and/or N(lower-alkyl)₂.

The term “lower-alkyl”, alone or in combination with other groups,refers to a branched or straight-chain monovalent alkyl radical of oneto seven carbon atoms, preferably one to four carbon atoms. This term isfurther exemplified by such radicals as methyl, ethyl, n-propyl,isopropyl, n-butyl, s-butyl, t-butyl and the like. A lower-alkyl groupmay have a substitution pattern as described earlier in connection withthe term “alkyl”.

The term “cycloalkyl” refers to a monovalent carbocyclic radical of 3 to10 carbon atom(s), preferably 3 to 6 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, or cyclohexyl. Cycloalkyl in which one or more—CH₂— group is replaced by O, S, NH and/or N(lower-alkyl) are referredto as “heterocycloalkyl”. Examples of heterocycloalkyl groups are e.g.tetrahydrofuryl, pyrrolidinyl, piperidyl, and morpholinyl.

The term “alkoxy” refers to the group R′—O—, wherein R′ is an alkyl. Theterm “lower-alkoxy” refers to the group R′—O—, wherein R′ is alower-alkyl. The term “thio-alkoxy” refers to the group R′—S—, whereinR′ is an alkyl. The term “thio-lower-alkoxy” refers to the group R′—S—,wherein R′ is a lower-alkyl.

The term “alkenyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 20, preferably up to 16 carbon atoms, morepreferrably up to 10 carbon atoms. Lower-alkenyl groups as describedbelow also are preferred alkenyl groups. The term “lower-alkenyl” refersto a straight-chain or branched hydrocarbon residue comprising anolefinic bond and up to 7, preferably up to 4 carbon atoms, such as e.g.2-propenyl. An alkenyl or lower-alkenyl group may have a substitutionpattern as described earlier in connection with the term “alkyl”.

The term “alkadienyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising 2olefinic bonds and up to 20, preferably up to 16 carbon atoms, morepreferably up to 10 carbon atoms. Lower-alkadienyl groups as describedbelow also are preferred alkadienyl groups. The term “lower-alkadienyl”refers to a straight-chain or branched hydrocarbon residue comprising 2olefinic bonds and up to 7 carbon atoms. An alkadienyl orlower-alkadienyl group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “alkinyl”, alone or in combination with other groups, standsfor a straight-chain or branched hydrocarbon residue comprising a triplebond and up to 20, preferably up to 16 carbon atoms. The term“lower-alkinyl” refers to a straight-chain or branched hydrocarbonresidue comprising a triple bond and up to 7, preferably up to 4 carbonatoms, such as e.g. 2-propinyl. An alkinyl or lower-alkinyl group mayhave a substitution pattern as described earlier in connection with theterm “alkyl”.

The term “alkylene” refers to a straight chain or branched divalentsaturated aliphatic hydrocarbon group of 1 to 20 carbon atoms,preferably 1 to 16 carbon atoms. The term “lower-alkylene” refers to astraight chain or branched divalent saturated aliphatic hydrocarbongroup of 1 to 7, preferably 1 to 6 or 3 to 6 carbon atoms. Straightchain alkylene or lower-alkylene groups are preferred. An alkylene orlower-alkylene group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “alkenylene” refers to a straight chain or branched divalenthydrocarbon group comprising an olefinic bond and up to 20 carbon atoms,preferably up to 16 carbon atoms. The term “lower-alkenylene” refers toa straight chain or branched divalent hydrocarbon group comprising anolefinic bond and up to 7, preferably up to 5, C-atoms. Straight chainalkenylene or lower-alkenylene groups are preferred. An alkenylene orlower-alkenylene group may have a substitution pattern as describedearlier in connection with the term “alkyl”.

The term “aryl” relates to the phenyl or naphthyl group, preferably thephenyl group, which can optionally be mono- or multiply-substituted bylower-alkyl, lower-alkinyl, dioxo-lower-alkylene (forming e.g. abenzodioxyl group), halogen, hydroxy, CN, CF₃, NH₂, N(H, lower-alkyl),N(lower-alkyl)₂, aminocarbonyl, carboxy, NO₂, lower-alkoxy,thio-lower-alkoxy, lower-alkylcarbonyl, lower-alkylcarbonyloxy,lower-alkoxycarbonyl, aryl, and/or aryloxy. Preferred substituents arehalogen, CF₃, NO₂, CN, lower-alkyl, lower-alkoxy, thio-lower-alkoxy,lower-alkoxycarbonyl, and/or lower-alkylcarbonyl. More preferredsubstituents are fluorine and chlorine.

The term “heteroaryl” refers to an aromatic 5- or 6-membered ring whichcan comprise 1, 2 or 3 atoms selected from nitrogen, oxygen and/orsulphur such as furyl, pyridyl, 1,2-, 1,3- and 1,4-diazinyl, thienyl,isoxazolyl, oxazolyl, imidazolyl, or pyrrolyl. The term “heteroaryl”further refers to bicyclic aromatic groups comprising two 5- or6-membered rings, in which one or both rings can contain 1, 2 or 3 atomsselected from nitrogen, oxygen or sulphur such as e,g, indol orchinolin, or partially hydrogenated bicyclic aromatic groups such ase.g. indolinyl. A heteroaryl group may have a substitution pattern asdescribed earlier in connection with the term “aryl”. Preferredheteroaryl groups are thienyl and pyridyl which can optionally besubstituted as described above, preferably with bromine.

The term “pharmaceutically acceptable salts” embraces salts of thecompounds of formula (I) with inorganic or organic acids such ashydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid,phosphoric acid, citric acid, formic acid, maleic acid, acetic acid,fumaric acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms. Preferred salts are formates, hydrochlorides, hydrobromidesand methanesulfonic acid salts.

The term “pharmaceutically acceptable esters” embraces esters of thecompounds of formula (I), in which hydroxy groups have been converted tothe corresponding esters with inorganic or organic acids such as nitricacid, sulphuric acid, phosphoric acid, citric acid, formic acid, maleicacid, acetic acid, succinic acid, tartaric acid, methanesulphonic acid,p-toluenesulphonic acid and the like, which are non toxic to livingorganisms.

In detail, the present invention relates to compounds of formula (I)

wherein

-   U is O or a lone pair,-   V is a) O, S, NR¹, or CH₂, and L is lower-alkylene or    lower-alkenylene, b) —CH═CH— or —C≡C—, and L is lower-alkylene or a    single bond,-   W is CO, COO, CONR², CSO, CSNR², SO₂, or SO₂NR²,-   X is hydrogen or one or more optional halogen and/or lower-alkyl    substituents,-   m is 1 or 2,-   n is 0 to7,-   A¹ is hydrogen, lower-alkenyl, or lower-alkyl optionally substituted    by hydroxy, lower-alkoxy, or thio-lower-alkoxy,-   A² is cycloalkyl, cycloalkyl-lower-alkyl, lower-alkenyl,    lower-alkinyl, or lower-alkyl optionally substituted by hydroxy,    lower-alkoxy or thio-lower-alkoxy,-   A³ and A⁴ independently from each other are hydrogen or lower-alkyl,    or A¹ and A² or A¹ and A³ are bonded to each other to form a ring    and -A¹-A²- or -A¹-A³- are lower-alkylene or lower-alkenylene,    optionally substituted by R³, in which one —CH₂— group of -A¹-A²- or    -A¹-A³- can optionally be replaced by NR⁴, S, or O,-   A⁵ is cycloalkyl, cycloalkyl-lower-alkyl,    heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl,    heteroaryl-lower-alkyl, lower-alkyl optionally substituted with    hydroxy or lower-alkoxy, alkenyl optionally substituted with    hydroxy, or alkadienyl optionally substituted with hydroxy,-   R³ is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R⁵,R⁶), or    lower-alkyl optionally substituted by hydroxy,-   R¹, R², R⁴, R⁵, and R⁶ independently from each other are hydrogen or    lower-alkyl, and pharmaceutically acceptable salts and/or    pharmaceutically acceptable esters thereof.

Preferred are compounds of formula (I) and/or pharmaceuticallyacceptable salts thereof. Other preferred embodiments relate tocompounds of formula (I) wherein U is a lone pair or to compounds offormula (I) wherein U is O.

Each of the definitions of V given above, a) and b), individuallyconstitutes a preferred embodiment of the present invention. Further,each of the definitions of L, lower-alkylene, lower-alkenylene and asingle bond, individually constitutes a preferred embodiment of thepresent invention. Compounds as described above in which V is O or CH₂and L is lower-alkylene or lower-alkenylene relate to a furtherpreferred embodiment of the present invention. Other preferred compoundsare those, wherein V is —C≡C— and L is lower-alkylene or a single bond.Compounds as described above, wherein n is 0 also relate to a preferredembodiment of the present invention. Compounds as described above, inwhich the number of carbon atoms of L and (CH₂)_(n) together is 10 orless, more preferably 7 or less, are also preferred. The groups ofcompounds as described above, in which m is 1 or m is 2 individuallyrelate to a preferred embodiment of the present invention.

Other preferred compounds of the present invention are those in which A¹represents lower-alkyl, preferrably those in which A¹ is methyl orethyl. Another group of preferred compounds of the present invention arethose in which A² represents lower-alkenyl, or lower-alkyl optionallysubstituted by hydroxy or lower-alkoxy, with those compounds wherein A²represents 2-propenyl or 2-hydroxy-ethyl being especially preferred.

Compounds of formula (I), wherein A¹ and A² are bonded to each other toform a ring and -A¹-A²- is lower-alkylene or lower-alkenylene,optionally substituted by R³, in which one —CH₂— group of -A¹-A²- canoptionally be replaced by NR⁴, S, or O, wherein R³ and R⁴ are as definedabove are also preferred. In compounds wherein A¹ and A² are bonded toeach other to form a ring, said ring is preferrably a 4-,5-, or6-membered ring such as e.g. piperidinyl or pyrrolidinyl.

A further preferred embodiment of the present invention relates tocompounds of formula (I), wherein A³ and/or A⁴ represent hydrogen.

Compounds of formula (I), wherein A⁵ cycloalkyl, cycloalkyl-lower-alkyl,heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl,heteroaryl-lower-alkyl, or lower-alkyl optionally substituted withhydroxy or lower-alkoxy represent a preferred embodiment of the presentinvention. Other preferred compounds are those in which A⁵ is phenyl orbenzyl, optionally substituted by 1 to 3 substituents independentlyselected from the group concisting of fluorine and chlorine, or whereinA⁵ is lower-alkyl, with those compounds wherein A⁵ is phenyl,4-fluoro-phenyl, 4-chloro-phenyl, butyl, or pentyl being particularlypreferred. Another preferred group relates to compounds wherein X ishydrogen. Another preferred group relates to compounds wherein X isfluorine.

Compounds in which R² is hydrogen are also preferred. A furtherpreferred embodiment of the present invention relates to those compoundsas defined above, wherein W is COO, CONR², CSO, or CSNR² and R² ishydrogen.

Preferred compounds of general formula (I) are those selected from thegroup consisting of:

-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (2,4-difluoro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid p-tolylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (4-bromo-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (2,4-dimethoxy-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (4-methoxy-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid naphthalen-2-ylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (4-acetyl-phenyl)-amide,-   {5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-bromo-phenyl)-methanone,-   3-{5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbonyl}-benzonitrile,-   {5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-fluoro-phenyl)-methanone,-   {5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(5-bromo-thiophen-2-yl)-methanone,-   {5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-(4-chloro-phenyl)-methanone,-   {5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indol-1-yl}-phenyl-methanone,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid (4-chloro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid cycloheptylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid cyclohexylmethyl-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid 4-chloro-benzylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid(4-trifluoromethyl-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid 4-fluoro-benzylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-(4-fluoro-phenyl)ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-p-tolyl ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-phenyl ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid    phenylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid    (4-chloro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid    (2,4-difluoro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-sulfonic acid    (4-fluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (2,4-difluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid p-tolylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (4-bromo-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (2,4-dimethoxy-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (4-methoxy-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid naphthalen-2-ylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid (4-acetyl-phenyl)-amide,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-bromo-phenyl)-methanone,-   3-{5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbonyl}-benzonitrile,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-fluoro-phenyl)-methanone,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(5-bromo-thiophen-2-yl)-methanone,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-chloro-phenyl)-methanone,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-phenyl-methanone,-   {5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indol-1-yl}-(4-trifluoromethyl-phenyl)-methanone,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (4-chloro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid cycloheptylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid cyclohexylmethyl-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid 4-chloro-benzylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid(4-trifluoromethyl-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid 4-fluoro-benzylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid benzylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid cyclohexylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid O-(4-fluoro-phenyl)ester,-   Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}-methyl-amine,-   Allyl-{5-[1-(4-bromo-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}-methyl-amine,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-chloro-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid ethyl ester,-   Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amine,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester,-   Allyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-pentyl}-methyl-amine,-   6-[3-(Allyl-methyl-amino)-propoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-chloro-phenyl ester,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-chloro-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-methoxy-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid p-tolylamide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid naphthalen-1-ylamide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (2,4-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-fluoro-3-trifluoromethyl-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (2,4-dimethoxy-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-methylsulfanyl-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-bromo-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid benzylamide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-butyl-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-acetyl-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-chloro-phenyl ester.-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-chloro-phenyl ester,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid p-tolylamide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-bromo-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-butyl-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-bromo-phenyl ester,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-fluoro-phenyl ester,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid p-tolyl ester,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid hexyl ester,-   3-{6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,-   {6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,-   {6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,-   {6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-methoxy-phenyl ester,-   3-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,-   1-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-2-(2,4-difluoro-phenyl)-ethanone,-   1-(4-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-ethanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(3-chloro-phenyl)-methanone,-   1-{6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-2-)4-fluoro-phenyl)-ethanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-chloro-phenyl)-methanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-trifluoromethyl-phenyl)-methanone,-   {6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-pyridin-3-yl-methanone,-   {6-[⁴-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-3-methyl-phenyl)-methanone,-   6-[4-(allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-nitro-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid hexyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-bromo-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid isobutyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-methoxy-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid p-tolyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-methoxycarbonyl-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid butyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid 4-fluoro-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid phenethyl-amide,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    4-chloro-phenyl ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    benzyl ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    4-bromo-phenyl ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    hexyl ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    (4-fluoro-phenyl)-amide,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    p-tolylamide,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    (4-bromo-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (2,4-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid p-tolylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-bromo-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (2,4-dimethoxy-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-methoxy-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid naphthalen-2-ylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-acetyl-phenyl)-amide,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    4-fluoro-phenyl ester,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-bromo-phenyl)-methanone,-   3-    {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbonyl}-benzonitrile,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-fluoro-phenyl)-methanone,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(5-bromo-thiophen-2-yl)-methanone,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-chloro-phenyl)-methanone,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-phenyl-methanone,-   {6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinolin-1-yl}-(4-trifluoromethyl-phenyl)-methanone,-   (4-Bromo-phenyl)-[6-(4-diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-methanone,-   3-[6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbonyl]-benzonitrile,-   [6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-(4-fluoro-phenyl)-methanone,-   (5-Bromo-thiophen-2-yl)-[6-(4-diethylamino-butoxy)-3,4-dihydro-2H-quinolin-1-yl]-methanone,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid (4-chloro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid cycloheptylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid cyclohexylmethyl-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid 4-chloro-benzylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid (4-trifluoromethyl-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid 4-fluoro-benzylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid benzylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid cyclohexylamide,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbothioic    acid O-(4-fluoro-phenyl)ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid O-(4-fluoro-phenyl)ester,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid O-phenyl ester,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid phenylamide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid(4-chloro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,4-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid(4-fluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (4-chloro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    p-tolylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (4-cyano-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (4-methoxy-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (3,4-difluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (3-fluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (2,4-difluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (2,5-difluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    (4-bromo-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-sulfonic acid    phenylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (3-methyl-butyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid(furan-2-ylmethyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid ethylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid butylamide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (2-methyl-butyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (2-methoxy-ethyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (4-butyl-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid(tetrahydro-furan-2-ylmethyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-chloro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-fluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-bromo-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid(p-tolyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (3,4-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-trifluoromethyl-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (3-fluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-cyano-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,4-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-methoxy-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,5-difluoro-phenyl)-amide,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid(phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-chloro-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-cyano-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (3-fluoro-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-bromo-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-methoxy-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,4-difluoro-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid p-tolylamide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-fluoro-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,5-difluoro-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-trifluoromethyl-phenyl)-amide,-   6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (3,4-difluoro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid (4-chloro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-cyano-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carbothioic    acid cycloheptylamide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-methoxy-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-chloro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,5-difluoro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (4-bromo-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (2,4-difluoro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid p-tolylamide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid butylamide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid (3-fluoro-phenyl)-amide,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-sulfonic    acid phenylamide,-   5-[4-(Allyl-methyl-amino)-but-2-enyloxy]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester,-   5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester,-   5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carboxylic    acid tert-butyl ester,-   6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester,-   6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester,-   6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid    tert-butyl ester, and-   6-[5-(Allyl-methyl-amino)-pentyl]-3,4-dihydro-2H-quinoline-1-carboxylic    acid tert-butyl ester and pharmaceutically acceptable salts and/or    pharmaceutically acceptable esters thereof.

Further preferred compounds of general formula (I) are those selectedfrom the group consisting of

-   5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   6-Fluoro-5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pent-1-ynyl}-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   5-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pent-1-ynyl}-6-fluoro-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanol,-   2-(Ethyl-{5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanol,-   6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid phenyl ester,-   2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol,    and pharmaceutically acceptable salts and/or pharmaceutically    acceptable esters thereof.

Further particularly preferred compounds of general formula (I) arethose selected from the group consisting of

-   5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   5-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pent-1-ynyl}-6-fluoro-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid phenyl ester, and pharmaceutically acceptable salts and/or    pharmaceutically acceptable esters thereof.

Still more preferred embodiments of the invention are those of generalformula (VII)

wherein

-   V is O or CH₂;-   L is lower-alkylene or lower-alkenylene;-   W is COO, CONH, CSNH or CSO;-   A¹ is hydrogen or lower-alkyl,-   A² is lower alkyl or lower alkenyl;-   m is 1 or 2; and-   A⁵ is lower alkyl, phenyl or lower alkyl phenyl, wherein the phenyl    group is optionally substituted with halogen;    and pharmaceuticaly acceptable salts and esters thereof.

Preferred compounds of general formula (VII) are those selected from thegroup consisting of

-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid O-(4-chloro-phenyl)ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid 4-chloro-phenyl ester,-   6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid 4-fluoro-benzylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid 4-chloro-benzylamide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic    acid (4-fluoro-phenyl)-amide,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid O-(4-fluoro-phenyl)ester,-   5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic    acid (4-chloro-phenyl)-amide,-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid (2-methyl-butyl)-amide, and-   5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic    acid butylamide, and pharmaceutically acceptable salts and/or    pharmaceutically acceptable esters thereof.

Compounds of formulas (I) and (VII) can have one or more asymmetriccarbon atoms and can exist in the form of optically pure enantiomers oras racemats. The invention embraces all of these forms.

It will be appreciated, that the compounds of general formula (I) inthis invention may be derivatised at functional groups to providederivatives which are capable of conversion back to the parent compoundin vivo.

The present invention also relates to a process for the manufacture ofcompounds as described above, which process comprises

reacting a compound of formula (II)

with a compound (A¹,A²,U)N—C(A³,A⁴)-L-M, wherein V is O, S or NR¹, M ismesylate, tosylate, triflate, Cl, Br or I, and U, A¹, A², A³, A⁴, A⁵, L,W, X, m, n and R¹ are as defined above, or wherein HV is mesylate,tosylate, triflate, Cl, Br or I, and M is OH, SH or NHR¹, and R¹ is asdefined above,or b) reacting a compound of formula (III)

with a compound NHA¹,A², wherein M is mesylate, tosylate, triflate, Cl,Br or I, and A¹, A², A³, A⁴, A⁵, L, V, W, X, m and n are as definedabove,or c) reacting a compound of formula (IV)

with a compound (A¹,A²,U)N—C(A³,A⁴)-L-C≡CH, wherein M is Br or F₃CO₂SO,and U, A¹, A², A³, A⁴, A⁵, L, W, X and m are as defined above,or d) reacting a compound of formula (V)

with a compound (A¹,A²,U)N—C(A³,A⁴)-L-M, wherein M is mesylate,tosylate, triflate, Cl, Br or I, and A¹, A², A³, A⁴, A⁵, W, U, L, X, mand n are as defined above,or e) hydrogenating a compound of formula (VI)

wherein V is —C≡C—, and A¹, A², A³, A⁵, A⁵, U, W, L, X, m and n are asdefined above, and optionally converting a compound according to any ofclaims 1 to 21 to a pharmaceutically acceptable salt,and optionally converting a compound according to any of claims 1 to 21,wherein U is a lone pair, to a corresponding compound wherein U is O.

The invention further relates to compounds of formula (I) as definedabove, when manufactured according to a process as defined above.

As described above, the compounds of formula (I) of the presentinvention can be used for the treatment and/or prophylaxis of diseaseswhich are associated with OSC such as hypercholesterolemia,hyperlipemia, arteriosclerosis, vascular diseases, mycoses, parasiteinfections and gallstones, and/or treatment and/or prophylaxis ofimpaired glucose tolerance, diabetes, tumors and/or hyperproliferativedisorders, preferably for the treatment and/or prophylaxis ofhypercholesterolemia and/or hyperlipemia. Hyperproliferative skin andvascular disorders particularly come into consideration ashyperproliferative disorders.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutic active substances, particularly as therapeutic activesubstances for the treatment and/or prophylaxis of of diseases which areassociated with OSC such as hypercholesterolemia, hyperlipemia,arteriosclerosis, vascular diseases, mycoses, parasite infections,gallstones, tumors and/or hyperproliferative disorders, and/or treatmentand/or prophylaxis of impaired glucose tolerance and diabetes,preferably for the treatment and/or prophylaxis of hypercholesterolemiaand/or hyperlipemia.

In another embodiment, the invention relates to a method for thetreatment and/or prophylaxis of diseases which are associated with OSCsuch as hypercholesterolemia, hyperlipemia, arteriosclerosis, vasculardiseases, mycoses, parasite infections, gallstones, tumors and/orhyperproliferative disorders, and/or treatment and/or prophylaxis ofimpaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia, whichmethod comprises administering a compound as defined above to a humanbeing or animal.

The invention further relates to the use of compounds as defined abovefor the treatment and/or prophylaxis of diseases which are associatedwith OSC such as hypercholesterolemia, hyperlipemia, arteriosclerosis,vascular diseases, mycoses, parasite infections, gallstones, tumorsand/or hyperproliferative disorders, and/or treatment and/or prophylaxisof impaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia.

In addition, the invention relates to the use of compounds as definedabove for the preparation of medicaments for the treatment and/orprophylaxis of diseases which are associated with OSC such ashypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases,mycoses, parasite infections, gallstones, tumors and/orhyperproliferative disorders, and/or treatment and/or prophylaxis ofimpaired glucose tolerance and diabetes, preferably for the treatmentand/or prophylaxis of hypercholesterolemia and/or hyperlipemia. Suchmedicaments comprise a compound as defined above.

The compounds of formula (I) can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to the person skilled in the art. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below or in the examples or by methods known in the art,e.g. by methods described in: Richard J. Sundberg Indoles (BestSynthetic Methods), Series Editor A. R. Katritzky, O. Meth-Cohn, C. W.Rees, Acedemic Press, San Diego 1996, or inHouben-Weyl Methoden derOrganischen Chemie, R. P. Kreker, Ed., Georg Thieme Verlag, Stuttgart,1994 , or The Chemistry of Heterocyclic Compounds. A Series ofMonographs, Vol. 32, Quinolines. Part 1–3, Weissenberger, E. C. Taylor,G. Jones, Eds, Wiley, London.

Scheme 1

If starting material 1 is a tetrahydroquinoline derivative (m=2), it maybe derived from the corresponding quinoline derivative by hydrogenationwith PtO₂ in a suitable solvent such as methanol, ethanol. If startingmaterial 1 is an indoline derivative (m=1), it may be derived from thecorresponding indole derivative for example by treatment with NaCNBH₃ inacetic acid or trifluoro acetic acid or by employing other methods knownin the art.

Derivative 1 is either N-protected (e.g. (BOC)₂O, CH₂Cl₂) to yieldcompound 2 or is directly converted to the desired A⁵W-substitutedderivative 2 using one of the methods described later for compound 5.

Deprotection of the V-group can be achieved, if 2 is a5-benzyloxyindoline derivative, by hydrogenation with e.g. Pd/C insolvents like methanol, ethanol or ethyl acetate, if 2 is a5-methoxy-indoline derivative, by treatment for example withlithium-tri-sec-butylborohydride in THF. For V═S, NR¹ or V═O and n>0,deprotection using procedures known in the art (step c) yields thebuilding block 3.

Alkylation of the phenol/thiophenol 3 (V═O, S, n=0) is accomplished inacetone or DMF with K₂CO₃ and a suitable dihaloalkane or dihaloalkene(halogene is here represented by bromine, but can also be chlorine oriodine. It is also possible to use mesylates, tosylates or triflatesinstead of halogenides) at reflux to yield halogenide 4 (step c). Forthe preparation of derivatives 4 (V═O, n>0), the alcohol 3 can betreated with α,ω-dihaloalkanes or α,ω-dihaloalkenes under phase transferconditions e.g. α,ω-dihaloalkanes/dihaloalkenes, NaOH, nBu₄NHSO₄. ForV═S, O or NR¹, the derivative 3 may be treated with α,ω-dihaloalkane inthe presence of NaH in DMF 0° C. to RT to yield bromide 4. For shorteralkanes (methyl, ethyl), the method of choice is the in situ generationof the haloalkane-triflate (from the corresponding haloalkanol withtrifluoromethansulfonic anhydride/2,6-di-tert-butylpyridine in CH₂Cl₂ at0° C.). This haloalkane-triflate may then be reacted with 3 in thepresence of a base such as 2,6-di-tert-butylpyridine in nitromethane at60° C. to yield bromide 4 [analogously to a procedure of Belostotskii,Anatoly M.; Hassner, Alfred. Synthetic methods. 41. Etherification ofhydroxysteroids via triflates. Tetrahedron Lett. (1994), 35(28), 5075].

Compound 4 can be converted to the amine 5 with an excess of thecorresponding amine NHA¹A² in a suitable solvent such as DMA, DMF, MeOHat RT or at 50–65° C. or by treatment with NHA¹A², NaH in solvents suchas DMF or THF (step d).

Compound 5 can be N-deprotected using TFA in CH₂Cl₂ for BOC-groups or byhydrogenation in methanol, ethanol or ethyl acetate with Pd/C forZ-groups.

The resulting amine (not shown in scheme 1) may be treated according toone of the following procedures to yield the appropriate A⁵W-substitutedderivative 5 (separation by HPLC was necessary in some cases).

Sulfonamides: Sulfonylation of the amines is done in dioxane or CH₂Cl₂with Huenig's base and a sulfonyl chloride over night at RT to yield thesulfonamide 5.

Carbamates: The amines may be reacted with A⁵OCOCl/Huenig's base orpyridine in dioxane, THF, DMF or CH₂Cl₂. Alternatively, thechloroformates may be prepared in situ by treatment of A⁵OH with Cl₃COClin the presence of quinoline followed by reaction with the amines in thepresence of Huenig's base.

Thiocarbamates: The amines may be reacted with A⁵OCSCl in dioxane.

Ureas: The amines may be reacted with isocyanate in dioxane at roomtemperature.

Thioureas: The amines may be reacted with isothiocyanate in dioxane atroom temperature.

Amides: The amines may be reacted with A⁵COOH/EDCI/DMAP (with anhydrideformation, and subsequent addition of the starting amine at −10° C. toroom temperature) or alternatively with A⁵COOH/EDCI/DMAP orA⁵COOH/Huenig's base/EDCI/HOBT in DMF, dioxane or CH₂Cl₂ at roomtemperature.

Sulfamides: The amines may be reacted with sulfamoyl chlorides indioxane in the presence of an excess of triethylamine to yield sulfamide5. The sulfamoyl chlorides can be prepared from A⁵NH₂ and chlorosulfonicacid in CH₂Cl₂ at 0° C. to room temperature followed by reaction withPCl₅ in toluene at 75° C. Alternatively, the sulfamoyl chlorides can besynthesized in acetonitrile with A⁵NH₂ and sulfuryl chloride at 0° C. to65° C.

Alternatively, the compound 3 may be converted to the amine 5 byattaching the pre-assembled fragmentA¹A²NC(A³A⁴)LV-OMes/halogenide/triflates, which can be synthesised byknown methods (shown e.g. in Scheme 2), using alkylating conditions(step f). Compounds 3 (V═O, n>0) can also be mesylated (V═OMes) and thenreacted with A¹A¹NC(A³A⁴)L-VH (synthesis as described in Scheme 2) ine.g. DMF with NaH as base to yield 5 (with V═O, S, NR¹).

Amine 5 may be converted to a salt or to the N-oxide 6 (step e). ForN-oxide 6 (V═O) a mixture of hydrogen peroxide urea adduct and phthalicanhydride in CH₂Cl₂ at RT may be used. For the preparation of theN-oxides 6 (V═S or NR¹) an alternative route has to be employed (stepg): Oxidation of the pre-assembled fragmentA¹A²NC(A³A⁴)L-OMes/halogenide to the corresponding N-oxide derivative,followed by alkylation of the compound 3 to give compound 6 directly.

If WA⁵ is a protective group, this may be cleaved as described forderivative 5 and the final moieties WA⁵ may be introduced as describedabove.

Scheme 2

Scheme 2 shows the synthesis of amino-VH sidechain 24 that may be usedfor the synthesis of compounds with the corresponding V-spacers (V═NR¹,S, or O). α,ω-dihaloalkane, mesyl-alkanyl-halogenide, α,ω-dihaloalkene,mesyl-alkenyl-halogenide 21 may be treated with a suitable protectedamine (HNR¹-PG, PG=protecting group, e.g. BOC) in DMA or a thiol (HS-PGe.g., triphenylmethanethiol) in the presence of NaH in DMA to yield thecompound 22(step a). Treatment with the amine A¹A²NH yields the S- orN-protected amine 23 (step b) or in the case of α,ω-haloalkanol orα,ω-haloalkenol 21 directly amino-alcohol 24. N-deprotection withprocedures known in the art e.g. TFA in CH₂Cl₂ yields the amine sidechain 24 (step c). The deprotection of the thiol moiety in 23 may beachieved with TFA/triisopropylsilane in CH₂Cl₂ at 0° C. to RT to yieldthe aminothiol 24 (step c). Aminoalkanol 24 can be transformed furtherto mesylate 25 (step d).

Scheme 3

In Scheme 3, the preparation of compounds of formula 6, in which Vrepresents —CH₂—, —CH═CH— or —C≡C— is outlined. The starting material isderivative3, which may be converted to the triflate 32a in pyridine withtrifluoromethanesulfonic anhydride at 0° C. to RT (step a).Sonogashira-coupling (step b) of the triflate 32a and a suitable alkynolor alkynechloride in piperidine with Pd(PPh₃)₄/CuI at 45° C. to 80° C.in analogy to a literature procedure yields alcohol 33a or chloride 33b[Stara, Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman,David; Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes.The synthesis of phenylacetylenes and symmetrical or unsymmetrical1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4),649–672.].

Alternatively, the alkynes 33a or 33b can be prepared by Sonogashirareaction of the bromo-derivatives 32b with the corresponding alkynols oralkynechlorides.

Mesylation of alcohol 33a with methanesulfonylchloride e.g. in solventssuch as pyridine or CH₂Cl₂ with bases like triethylamine or Huenig'sbase optionally in the presence of DMAP (reaction step c) and subsequentamination (reaction step d) of the resulting mesylate 34 with a suitableamine NHA¹A² in a solvent like DMA, DMF or MeOH at RT or at 50–65°yields the amine 6. Alcohol 33a can also be treated withtrifluoromethane sulfonic acid anhydride and Huenig's base at −15° C. inCH₂Cl₂ (in situ generation of the corresponding triflate) followed bytreatment with the corresponding amine NHA¹A² at −15° C. to RT. This isespecially the method of choice for but-3-yn-1-ol-derivatives 33a.Chloride 33b can be transformed directly or via iodide (Finkelsteinreaction) to the amine 6, as described above (step d). Compounds 6 inwhich V is —CH₂— or —CH═CH— can be obtained by hydrogenation of compound6 in solvents like MeOH or EtOH with Pt₂O.H₂O or Pd/C (yields thesaturated analogue 6) or by selective hydrogenation with other knownmethods (e.g. Lindlar or DIBAH, REDAL) (yields the double bond analogue6). Optionally, the hydrogenation described above can be performed at anearlier stage e.g. the alcohol 33a or mesylate 34.

Alternatively, the group A¹A²NC(A³A⁴C)-L-acetylene can be synthesised byknown methods and attached to compound 32a or 32b(Sonogashira-coupling), to yield the compounds of the present invention6 (reaction step f).

Compounds of the formula 5 (n>0) may be synthesised by Swern oxidationof the alcohol 3 (V═O and n>0) to yield the corresponding aldehyde 35(step g) as an intermediate. The aldehyde 35 may be treated withtriphenylphosphine, tetra-bromo-methane and triethylamine in CH₂Cl₂ at0° C. to RT to yield 2,2-Dibromo-vinyl derivative 36 (step h).Rearrangement with n-BuLi (ca 1.6 M in hexane) in THF at −78° C.,followed by reaction with formaldehyde (−78° C. to RT) leads to thepropargyl alcohol 37a (step i, side chain extension through applicationof the Corey-Fuchs method), following conditions described in: Marshall,James A.; Bartley, Gary S.; Wallace, Eli M. Total Synthesis of thePseudopterane (−)-Kallolide B, the Enantiomer of Natural (+)-KallolideB. J. Org. Chem. (1996), 61(17), 5729–5735; and Baker, Raymond; Boyes,Alastair L.; Swain, Christopher J. Synthesis of talaromycins A, B, C,and E. J. Chem. Soc., Perkin Trans. 1 (1990), (5), 1415–21.

For longer side chains, the rearrangement is performed with n-BuLi (ca1.6 M in hexane) in THF at −78° C. as above, followed by addition of aco-solvens such as DMPU and reaction with O-protected 1-bromo-alcohols(e.g. 1-bromo-n-tetrahydro-pyaranyloxyalkane) to yield the O-protectedcompounds 37b (step i). O-protected compounds 37b can be deprotected tothe corresponding alkynol 37a (in MeOH at 50–60° C., in the presence ofcatalytic amount of pyridinium toluene-4-sulfonate). Alcohol 37a can bereacted with Huenig's base/trifluoromethane sulfonic acid anhydride at−15° C. in CH₂Cl₂ (in situ generation of the corresponding triflate)followed by treatment with Huenig's base and the corresponding amineNHA¹A² at −15° C. to RT to yield amine 6. Alternatively, mesylation ofalcohol 37a with methanesulfonylchloride, pyridine and DMAP in CH₂Cl₂ at0° C. to RT yields mesylate 38. Conversion of the mesylate 38 to theamine 6 can be accomplished with an excess of the corresponding amineNHA¹A² in DMA at RT or as described above (step l).

Compounds 6 in which V is —CH₂— or —CH═CH— can be obtained byhydrogenation of compound 5 itself or the intermediates 37a, 37b or 38.The hydrogenation may be performed in EtOH or MeOH with Pt₂O·H₂O or Pd/C(yields the saturated analogues 6, 37a, 37b, or 38) or by selectivehydrogenation to obtain the double bond by other known methods (e.g.Lindlar or DIBAH, REDAL) and transforming the intermediates afterwardsto 6.

Alternatively, for the introduction of the group A¹A²N(A³A⁴C)L in whichA³ and/or A⁴ are not H, the following steps have to be performedstarting from compound 36 (step m or steps i and l): for L=loweralkanes, the building block A¹A²N(A³A⁴C)L-halogenide/mesylate issynthesised by known methods (or in analogy to the methods described inScheme 2) and introduced (step m) under the same condition as describedabove for step i. For L=single bond, the introduction of the groupA¹A²N(A³A⁴C) with A³ and/or A⁴ not H, a two step procedure has to befollowed: first the rearrangement of 36 with n-BuLi (ca 1.6 M in hexane)in THF at −78° C., followed by reaction with the corresponding aldehyde(A³ or A⁴-COH) or ketone (A³COA⁴, at −78° C. to RT) leads to the A³A⁴substituted propargyl alcohol 37a (step i) which is e.g. mesylated ortransformed to a phosphorester or a chloride (not shown) and reactedwith the desired A¹A²-substituted-amine in the presence ofTetrakis(triphenylphosphine)palladium (for the phosphorester) orCu(I)Cl/Cu bronze and Huenig's base (for the chloride) to yield thedesired A³,A⁴-substituted compound 5 (step 1). (see: Bartlett, Paul A.;McQuaid, Loretta A. Total synthesis of (±)-methyl shikimate and(±)-3-phosphoshikimic acid. J. Am. Chem. Soc. (1984), 106(25), 7854–60and Cooper, Matthew A.; Lucas, Mathew A.; Taylor, Joanne M.; Ward, A.David; Williamson, Natalie M. A convenient method for the aromaticamino-Claisen rearrangement of N-(1,1-disubstituted-allyl)anilines.Synthesis (2001), (4), 621–625.)

Amine 6 may be converted to a salt or to the N-oxide 6 using a mixtureof hydrogen peroxide urea adduct and phthalic anhydride in CH₂Cl₂ at RT(step e).

If WA⁵ is a protecting group, this may be cleaved and the final moietiesWA⁵ may be introduced as described for derivative 5 in scheme 1.

The following tests were carried out in order to determine the activityof the compounds of formula I and their salts.

Inhibition of Human Liver Microsomal 2,3-oxidosqualene-lanosterolcyclase (OSC)

Liver microsomes from a healthy volunteer were prepared in sodiumphosphate buffer (pH 7.4). The OSC activity was measured in the samebuffer, which also contained 1 mM EDTA and 1 mM dithiothreitol. Themicrosomes were diluted to 0.8 mg/ml protein in cold phosphate buffer.Dry [¹⁴C]R,S-monooxidosqualene (MOS, 12.8 mCi/mmol) was diluted to 20nCi/μl with ethanol and mixed with phosphate buffer-1% BSA (bovine serumalbumin). A stock solution of 1 mM test substance in DMSO was diluted tothe desired concentration with phosphate buffer-1% BSA. 40 μl ofmicrosomes were mixed with 20 μl of the solution of the test substanceand the reaction was subsequently started with 20 μl of the [¹⁴C]R,S-MOSsolution. The final conditions were: 0.4 mg/ml of microsomal proteinsand 30 μl of [¹⁴C]R,S-MOS in phosphate buffer, pH 7.4, containing 0.5%albumin, DMSO <0.1% and ethanol <2%, in a total volume of 80 μl.

After 1 hour at 37° C. the reaction was stopped by the addition of 0.6ml of 10% KOH-methanol, 0.7 ml of water and 0.1 ml of hexane:ether (1:1,v/v) which contained 25 μg of non-radioactive MOS and 25 μg oflanosterol as carriers. After shaking, 1 ml of hexane:ether (1:1, v/v)was added to each test tube, these were again shaken and thencentrifuged. The upper phase was transferred into a glass test tube, thelower phase was again extracted with hexane:ether and combined with thefirst extract. The entire extract was evaporated to dryness withnitrogen, the residue was suspended in 50 μl of hexane:ether and appliedto a silica gel plate. Chromatographic separation was effected inhexane:ether (1:1, v/v) as the eluent. The Rf values for the MOSsubstrate and the lanosterol product were 0.91 and, respectively, 0.54.After drying, radioactive MOS and lanosterol were observed on the silicagel plate. The ratio of MOS to lanosterol was determined from theradioactive bands in order to determine the yield of the reaction andOSC inhibition.

The test was carried out on the one hand with a constant test substanceconcentration of 100 nM and the percentage OSC inhibition againstcontrols was calculated. The more preferred compounds of the presentinvention exhibit inhibitions larger than 50%. In addition, the test wascarried out with different test substance concentrations andsubsequently the IC₅₀ value was calculated, i.e. the concentrationrequired to reduce the conversion of MOS into lanosterol to 50% of thecontrol value. The preferred compounds of the present invention exhibitIC₅₀ values of 1 nM to 10 μM, preferrably of 1–100 nM.

The compounds of formula I and their pharmaceutically acceptable acidaddition salts can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions,

-   emulsions or suspensions, rectally, e.g. in the form of    suppositories, parenterally, e.g. in the form of injection solutions    or infusion solutions, or topically, e.g. in the form of ointments,    creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula I and their pharmaceuticallyacceptable acid addition salts, optionally in combination with othertherapeutically valuable substances, into a galenical administrationform together with suitable, non-toxic, inert, therapeuticallycompatible solid or liquid carrier materials and, if desired, usualpharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavour-improving agents, salts forvarying the osmotic pressure, buffer substances, solubilizers, colorantsand masking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula I can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 50 mg to about 500 mg, comes into consideration for theprevention and control of topical and systemic infections by pathogenicfungi. For cholesterol lowering and treatment of impaired glucosetolerance and diabetes the daily dosage conveniently amounts to between1 and 1000 mg, preferably 5 to 200 mg, for adult patients. Depending onthe dosage it is convenient to administer the daily dosage in severaldosage units.

The pharmaceutical preparations conveniently contain about 1–500 mg,preferably 5–200 mg, of a compound of formula I.

The following Examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES

Abbreviations:

AcOH=acetic acid, n-BuLi=n-Butyl lithium, CuI=copper iodide,DMF=N,N-dimethylformamide, Et₂O=ether=diethyl ether, EtOAc=ethylacetate, eq.=equivalents, Huenig's base=N,N-diisopropylethylamine,KOtBu=potassium tert. butylate, MeOH=methanol, NaOtBu=sodium tert.butylate, NEt₃=triethylamine, Pd/C=palladium on carbon,PdCl₂(PPh₃)₂=bis(triphenylphosphine)palladium(II) chloride,Pd(Ph₃P)₄=tetrakis(triphenylphosphine)palladium, RT=room temperature,THF=tetrahydrofuran, TFA=trifluoroacetic acid.

General Remarks

All reactions were performed under argon.

The purification of the final amines by preparative HPLC [e.g. RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile]yielded mixtures of the corresponding amino formate and thecorresponding halogenide or methanesulfonic acid salt which was used inthe reaction. The ratio was not always determined, the purity of thefinal amino salts was >80% after LC-MS.

Example 1

1.1

1,2,3,4-Tetrahydro-quinolin-6-ol can be prepared from quinolin-6-olaccording to Moore; Capaldi; J.Org.Chem., 29, 1964, 2860 or Hoenel,Michael; Vierhapper, Friedrich W.; J.Chem.Soc.Perkin Trans. 1, 1980,1933–1939.

1.2

To 750 mg (5 mmol) 1,2,3,4-Tetrahydro-quinolin-6-ol in 10 ml THF 950 mg(5 mmol) 4-chlorophenylchloroformate were added. The solution wasstirred at RT for 30 min, 0.5 ml (6 mmol) pyridine were added and thesolution was stirred for additional 30 min. The mixture was concentratedin vacuo and dissolved in EtOAc, water and 2M HCl was added. Theinorganic phase was extracted with EtOAc, the combined organic phaseswere washed with water and dried over Na₂SO₄. Column chromatography onsilica gel with CH₂Cl₂/MeOH 49:1 yielded 600 mg (40%)6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenylester as colorless gum, MS: 303 (M, 1Cl).

1.3

To 304 mg (1 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester in 4 ml DMF 420 mg (3 mmol) K₂CO₃ (powdered) and416 mg (2 mmol) 1,4-dibromobutene were added. The mixture was stirred at50° C. for 1 h, diluted with EtOAc and water. 2M HCl was added and theinorganic phase was extracted with EtOAc. The combined organic phaseswere washed with water and dried over Na₂SO₄. The crude-product waspurified by column chromatography on silica gel with hexane/EtOAc 9:1 to4:1 to yield 250 mg (46%)6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester as colorless gum, MS: 436 (MH⁺, 1Br, 1Cl).

1.4

To 245 mg (0.8 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester in 5 ml acetone 323 mg (2.3 mmol) K₂CO₃(powdered) and 0.21 ml (2.1 mmol) 1,3-dibromopropane were added. Themixture was stirred at reflux for 4 h, filtered and concentrated. Theresidue was dissolved in EtOAc and water, and the inorganic phase wasextracted with EtOAc. The combined organic phases were washed with waterand dried over Na₂SO₄. The crude product was purified by columnchromatography on silica gel with CH₂Cl₂ yielding 210 mg (61%)6-(3-Bromo-propoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester as colorless oil, MS: 424 (MH⁺, 1Br, 1Cl).

1.5

In analogy to example 1.4,6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenylester and 1,4-dibromobutane were converted to yield6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester as colorless oil, MS: 438 (MH⁺, 1Br, 1Cl);

1.6

In analogy to example 1.4,6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid 4-chloro-phenylester and 1,5-dibromopentane (80%) were converted to yield6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester as colorless oil, MS: 451 (M, 1Br, 1Cl).

1.7

To 153 mg (0.35 mmol)6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester in 3 ml DMF 71 mg (1 mmol) N-allylmethylamine and140 mg (1 mmol) K₂CO₃ (powdered) were added and the mixture was stirredat 60° C. for 1 h. The mixture was concentrated in vacuo, 8 ml acetonewere added, the suspension was filtered and the filtrate wasconcentrated. Column chromatography on silica gel with CH₂Cl₂/MeOH 9:1yielded 95 mg (64%)6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester as colorless oil, MS: 426 (M, 1Cl).

1.8

To 210 mg (0.49 mmol)6-(3-Bromo-propoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester in 5 ml DMF 191 μl (2 mmol) N-allylmethylamine and106 mg (4.2 mmol, 50% in hexane) NaH were added. The mixture was stirredat RT for 4 h and extracted with ether and water. The organic phase waswashed with water and dried over Na₂SO₄. Column chromatography on silicagel with CH₂Cl₂/MeOH 9:1 yielded 70 mg (34%)6-[3-(Allyl-methyl-amino)-propoxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester as colorless oil, MS: 415 (MH⁺, 1Cl).

1.9

In analogy to example 1.8,6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester and N-allylmethylamine were converted to yield6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester as colorless oil, MS: 443 (MH⁺, 1Cl).

1.10

240 mg (0.55 mmol)6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester and 260 μl (2.7 mmol) N-allylmethylamine werestirred in 5 ml DMF at RT for 3 h. The mixture was extracted with etherand water, the organic phase was washed with water and dried overNa₂SO₄. Purification by column chromatography on silica gel withCH₂Cl₂/MeOH 9:1 yielded 154 mg (66%)6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester as colorless oil, MS: 429 (MH⁺, 1Cl).

Example 2

2.1

To 9.7 g (65 mmol) 1,2,3,4-Tetrahydro-quinolin-6-ol in 90 ml CH₂Cl₂ 13.7g (62.8 mmol) di-tert.-butyl-dicarbonate were added. The solution wasstirred at 50° C. for 5 h and at RT over night. The mixture wasconcentrated and dissolved in Et₂O. A diluted aqueous solution of KHSO₄was added and the inorganic phase was extracted with Et₂O, the combinedorganic phases were washed with brine and dried over Na₂SO₄. Columnchromatography on silica gel with CH₂Cl₂/MeOH 9:1 yielded 16.2 g (99%)6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester aslight yellow crystals, MS: 249 (M).

2.2

To 11.6 g (46.5 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester in 200 ml acetone 18.6 g (134.8 mmol) K₂CO₃(powdered) and 13.7 g (115.7 mmol) 1,4-dibromobutane were added. Themixture was stirred at reflux for 4 h and at RT over night. The reactionmixture was filtered, and the filtrate was concentrated in vacuo. EtOAcand water were added, the inorganic phase was extracted with EtOAc andthe combined organic phases were washed with water and dried overNa₂SO₄. The crude product was purified by column chromatography onsilica gel with hexane/EtOAc 9:1 to yield 11.1 g (63%)6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butylester as colorless oil, MS: 383 (M, 1Br).

2.3

In analogy to example 2.2,6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl esterand 1,4-dibromobutene were converted to yield6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester as colorless oil, MS: 381 (M, 1Br);

2.4

In analogy to example 2.2,6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl esterand 1,5-dibromopentane were converted to yield6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester (63%) as colorless oil, MS: 397 (M, 1Br);

2.5

In analogy to example 2.2,6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl esterand 1,6-dibromohexane were converted to yield6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester (40%) as light green oil, MS: 412 (MH⁺, 1Br);

2.6

1.5 g (3.75 mmol)6-(5-Bromo-pentyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester were treated with 355 mg (5 mmol) N-allyl-methylamineand 830 mg (6 mmol) K₂CO₃ (powdered) in 8 ml DMF at 60° C. for 3 h. Themixture was concentrated in vacuo, dissolved in acetone and filtered.The filtrate was concentrated and purified by column chromatography onsilica gel with CH₂Cl₂/MeOH 19:1 to yield 1.05 g (72%)6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as colorless oil, MS: 389 (MH⁺).

2.7

In analogy to example 2.6,6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester and N-allyl-methylamine were converted to yield6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as colorless gum, MS: 403 (MH⁺).

2.8

In analogy to example 2.6,6-(4-Bromo-but-2-enyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester and N-allyl-methylamine were converted to yield6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as colorless oil, MS: 373 (MH⁺).

2.9

5.0 g (13.0 mmol)6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butylester were treated with 3.66 g (51.5 mmol) N-allyl-methylamine in 100 mlDMF at 50° C. for 30 min. The mixture was concentrated in vacuo,dissolved in Et₂O and water. The inorganic layer was extracted withEt₂O, and the combined organic phases were washed with water and driedover Na₂SO₄. Purification by column chromatography on silica gel withCH₂Cl₂/MeOH 10:1 yielded 3.6 g (74%)6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as light yellow oil, MS: 375 (MH⁺).

2.10

In analogy to example 2.9,6-(4-Bromo-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butylester and diethylamine were converted to yield6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester as colorless oil.

Example 3

3.1

3.64 g (9.7 mmol)6-[4-(Allyl-methyl-amino)-butoxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester in 5 ml CH₂Cl₂ were treated with 3.5 ml TFA at 0°C., and the solution was stirred at 40° C. for 1 h. The solution wasconcentrated and the residue dissolved in a mixture of a saturatedaqueous solution of NaHCO₃ and ether. The inorganic phase was extractedwith ether and the combined organic phases were washed with water anddried over Na₂SO₄ to yield 1.85 g (69%)Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine, MS:275 (MH⁺).

3.2

In analogy to example 3.1,6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester was converted to yieldAllyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amine(crude) as orange oil, MS: 273 (MH⁺).

3.3

In analogy to example 3.1,6-[5-(Allyl-methyl-amino)-pentyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester was converted to yieldAllyl-methyl-[5-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-pentyl]-amine(82%) as light yellow oil, MS: 289 (MH⁺);

3.4

In analogy to example 3.1,6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester was converted to yieldAllyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine (93%)as colorless gum, MS: 303 (MH⁺);

3.5

In analogy to example 3.1,6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester was converted to yieldDiethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine as lightbrown oil, MS: 277 (MH⁺).

3.6

To 54 mg (0.2 mmol)Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-aminein 2 ml CH₂Cl₂ 3 drops of Huenig's base and 527 mg (0.25 mmol)4-chlorobenzene sulfonylchloride were added. The solution was stirred atRT for 2 h, concentrated and purified by column chromatography on silicagel with CH₂Cl₂/MeOH 19:1 to yield 70 mg (78%)Allyl-{4-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-but-2-enyl}-methyl-amineas yellow oil, MS: 447 (MH⁺, 1Cl).

3.7

In analogy to example 3.6,Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine and4-chlorobenzene sulfonylchloride were converted to yieldAllyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yloxy]-pentyl}-methyl-amine(70%) as light yellow oil, MS: 462 (M, 1Cl).

3.8

To 60.4 mg (0.2 mmol)Allyl-methyl-[6-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-hexyl]-amine in 2ml CH₂Cl₂ 1 drop of Huenig's base and 57 mg (0.3 mmol) 4-chlorophenylchloroformate in 1 ml CH₂Cl₂ were added. The solution was stirred at RTfor 30 min, was concentrated and the residue was dissolved in ether anda saturated aqueous solution of NaHCO₃. The inorganic phase wasextracted with ether and the combined organic phases were washed withwater and dried over Na₂SO₄. Column chromatography on silica gel withCH₂Cl₂/MeOH 19:1 yielded 46 mg (50%)6-[6-(Allyl-methyl-amino)-hexyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid 4-chloro-phenyl ester as colorless oil, MS: 457 (MH⁺, 1Cl).

3.9

To 70 mg (0.25 mmol)Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine in 1.4 mlDMF 87 μl (0.5 mmol) Huenig's base and 54 μl (0.38 mmol) benzylchloroformate were added. The solution was stirred at RT over night, wasconcentrated and the residue was dissolved in ether and 0.1M NaOH. Theinorganic phase was extracted with ether and the combined organic phaseswere washed with water and dried over Na₂SO₄. Column chromatography onsilica gel with CH₂Cl₂/MeOH 5:1 yielded 40 mg (38%)6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidbenzyl ester as light yellow oil, MS: 411 (MH⁺).

3.10

In analogy to example 3.9,Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and4-chlorophenyl chloroformate were converted to yield6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-chloro-phenyl ester as colorless oil, MS: 431 (MH⁺, 1Cl).

3.11

In analogy to example 3.9,Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine andhexylchloroformate were converted to yield6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acidhexyl ester as colorless oil, MS: 405 (MH⁺).

3.12

In analogy to example 3.9,Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and4-bromophenyl chloroformate were converted to yield6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-bromo-phenyl ester as colorless oil, MS: 475 (MH⁺, 1Br).

3.13

In analogy to example 3.9,Diethyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-butyl]-amine and4-fluorophenylchloroformate were converted to yield6-(4-Diethylamino-butoxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid4-fluoro-phenyl ester as colorless oil, MS: 415 (MH⁺).

3.14

In analogy to example 3.9,Allyl-methyl-[4-(1,2,3,4-tetrahydro-quinolin-6-yloxy)-but-2-enyl]-amineand ethylchloroformate were converted to yield6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid ethyl ester as brown oil, MS: 345 (MH⁺).

Example 4

4.1

To 1.0 g (4 mmol) 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester in 2.5 ml pyridine 0.72 ml (43.6 mmol)trifluoromethanesulfonic anhydride was added at 0° C. and the mixturewas stirred at RT over night. Water and Et₂O were added, and theinorganic phase was extracted with Et₂O. The combined organic phaseswere washed with 2M HCl and water, and dried over Na₂SO₄. Columnchromatography on silica gel with hexane yielded 850 mg (56%)6-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester as yellow solid, MS: 381 (M).

4.2

To 850 mg (2.2 mmol)6-Trifluoromethanesulfonyloxy-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester in 5 ml piperidine, 128.0 mg (0.1 mmol)tetrakis(triphenylphosphine)palladium followed by 21.0 mg (0.1 mmol)copper iodide were added. The solution was evaporated and flushed withargon prior to the addition of 210 μl (2.2 mmol) 4-pentynol at 80° C.over a period of 45 min. Further 0.2 ml (2.1 mmol) 4-pentynol were addedand the solution was stirred for 2 h. The mixture was added to icewater, acidified with 2M HCl and extracted with ether. The combinedorganic phases were washed with water and dried over Na₂SO₄.Purification by column chromatography with CH₂Cl₂/MeOH 30:1 yielded 650mg (92%) 6-(5-Hydroxy-pent-1-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as light brown oil, MS: 316 (MH⁺).

4.3

850 mg (2.7 mmol)6-(5-Hydroxy-pent-1-ynyl)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester in 30 ml ethanol were hydrogenated in the presence of10% Pd/C over night. Purification by column chromatography yielded 450mg (68%) 6-(5-Hydroxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester as yellow oil, MS: 319 (M).

4.4

To 450 mg (1.43 mmol)6-(5-Hydroxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester in 15 ml CH₂Cl₂ 0.15 ml (1.9 mmol) methanesulfonylchloride and 0.63 ml (4.5 mmol) triethylamine were added at 0° C. Thesolution was stirred at RT for 2 h, was diluted with CH₂Cl₂, and 1M HClwas added. The inorganic layer was extracted with CH₂Cl₂ and thecombined organic phases were washed with water and dried over Na₂SO₄.Purification by column chromatography with CH₂Cl₂/MeOH 30:1 yielded 560mg (98%)6-(5-Methanesulfonyloxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as yellow oil, MS: 397 (M).

4.5

To 560 mg (1.4 mmol)6-(5-Methanesulfonyloxy-pentyl)-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester in 5 ml DMF were added 2.5 ml (26.0 mmol)N-allylmethylamine. The solution was stirred at 70° C. for 2 h,concentrated and dissolved in water and CH₂Cl₂. 2M NaOH was added andthe inorganic phase was extracted with CH₂Cl₂. The organic phase waswashed with water and dried over Na₂SO₄. Purification by columnchromatography with CH₂Cl₂/MeOH 20:1 yielded 470 mg (89%)6-[5-(Allyl-methyl-amino)-pentyl]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester as yellow oil, MS: 373 (MH⁺).

4.6

Treatment of6-[5-(Allyl-methyl-amino)-pentyl]-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester with TFA in analogy to example 3.1 yieldedAllyl-methyl-[5-(1,2,3,4-tetrahydro-quinolin-6-yl)-pentyl]-amine asyellow oil, MS: 272 (M).

4.7

Reaction ofAllyl-methyl-[5-(1,2,3,4-tetrahydro-quinolin-6-yl)-pentyl]-amine with4-Chlorobenzene-sulfonylchloride in analogy to example 3.6 yieldedAllyl-{5-[1-(4-chloro-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}-methyl-amineas light yellow oil, MS: 447 (MH⁺, 1Cl);

4.8

Treatment ofAllyl-methyl-[5-(1,2,3,4-tetrahydro-quinolin-6-yl)-pentyl]-amine with4-Bromobenzolsulfonylchloride in analogy to example 3.6 yieldedAllyl-{5-[1-(4-bromo-benzenesulfonyl)-1,2,3,4-tetrahydro-quinolin-6-yl]-pentyl}-methyl-amineas light brown oil, MS: 491 (MH⁺, 1Br).

Example 5

5.1

In analogy to the method described by Gordon W. Gribble, Joseph H.Hoffmann Synthesis 1977, 859–860, the following reaction was performed.To a precooled solution of 22.3 g (0.1 mol) 5-benzyloxyindole in 270 mlacetic acid, 19 g (0.3 mol) NaCNBH₃ were added. The solution was stirredat RT for 2 h, the volume was reduced to one third and poured into 300ml water. KOH was added under cooling and the solution was extractedwith ether. The combined organic phases were washed with water, driedover Na₂SO₄ and evaporated to yield 20.1 g (89%)5-Benzyloxy-2,3-dihydro-1H-indole as colorless oil, MS: 225 (M).

5.2

20 g (89 mmol) 5-Benzyloxy-2,3-dihydro-1H-indole in 250 ml CH₂Cl₂ weretreated with 20 g (91.6 mmol) di-tert.-butyldicarbonate at 0° C. for 1 hand at RT for 1 h. The mixture was concentrated and extracted with etherand 0.5 M HCl. The organic phase was washed with water and dried overNa₂SO₄. Trituration of the crude material with hexane yielded 23 g (71%)5-Benzyloxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester ascolorless solid, MS: 325 (M).

5.3

23 g (68.6 mmol) 5-Benzyloxy-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 250 ml methanol were hydrogenated with 2.5 g 10%Pd/C for 2 h. The suspension was filtered and the filtrate wasconcentrated and purified by column chromatography on silica gel withMeOH/EtOAc 1:1 yielding 14.4 g (90%)5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester ascolorless solid, MS: 235 (M).

5.4

514 mg (2.3 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 12 ml DMF were treated with 830 mg (6 mmol) powderedK₂CO₃ and 1070 mg (5 mmol) 1,4-dibromobutene. The suspension was stirredat 50° C. for 3 h, cooled to RT, diluted with ether and water. Theaqueous phase was extracted with ether, the organic phases were washedwith water and dried over Na₂SO₄. Column chromatography on silica gelwith hexane/EtOAc 9:1 yielded 270 mg (31%)5-(4-Bromo-but-2-enyloxy)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester as colorless solid, MS: 368 (MH⁺, 1Br).

5.5

214 mg (0.6 mmol)5-(4-Bromo-but-2-enyloxy)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 3 ml DMF were treated with 213 mg (3 mmol)N-allylmethylamine at 50° C. for 0.5 h. The mixture was extracted withether and water. The organic phase was washed with water and dried overNa₂SO₄ and evaporated to yield 180 mg (83%)5-[4-(Allyl-methyl-amino)-but-2-enyloxy]-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester as yellow oil, MS: 359 (MH⁺).

Example 6

6.1

Hydrogenation of 2.23 g (10 mmol) 5-benzyloxyindole in 25 ml acetic acidand 25 ml methanol with 500 mg 10% Pd/C yielded 2 g crude2,3-Dihydro-1H-indol-5-ol.

6.2

To 0.7 g (5 mmol) 2,3-Dihydro-1H-indol-5-ol in 10 ml THF, 1.7 ml (10mmol) N,N-diisopropylethylamine and 0.5 ml (3.6 mmol)4-chlorophenyl-chloroformate were added at 0° C. The solution wasstirred at RT for 1 h and concentrated in vacuo. The residue wasredissolved in ether/1M HCl, the inorganic phase was extracted withether and the combined organic phases were washed with water and driedover Na₂SO₄. Evaporation yielded 420 mg (29%)5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester ascolorless solid, MS: 289 (M, 1Cl).

6.3

290 mg (1 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acid4-chloro-phenyl ester in 5 ml acetone were treated with 320 mg (3 mmol)K₂CO₃ (powdered) and 0.23 ml (2 mmol) 1,4-dibromobutane. The suspensionwas stirred at 50° C. for 4 h, cooled to RT, and was diluted with etherand water. The aqueous phase was extracted with ether, the organicphases were washed with water and dried over Na₂SO₄. Columnchromatography on silica gel with hexane/EtOAc 9:1 yielded 210 mg (49%)5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenylester as colorless solid, MS: 423 (M, 1Br, 1Cl).

6.4

106 mg (0.25 mmol) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester in 2 ml DMF were treated with 71 mg (1 mmol)N-allylmethylamine at 50° C. for 2 h. The mixture was concentrated andpurified by column chromatography on silica gel with CH₂Cl₂/MeOH 19:1 togive 68 mg (66%)5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acid4-chloro-phenyl ester as colorless solid, MS: 415 (MH⁺, 1Cl).

Example 7

7.1

9.41 g (40 mmol) 5-Hydroxy-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 90 ml acetone were treated with 16.6 g (6 mmol)K₂CO₃ (powdered) and 17.3 g (5 mmol) 1,4-dibromobutane. The suspensionwas stirred at 50° C. for 4 h, cooled to RT, filtered and concentrated.Column chromatography on silica gel with CH₂Cl₂ yielded 8.8 g (60%)5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl esteras colorless solid, MS: 370 (MH⁺, 1Br).

7.2

8.8 g (24 mmol) 5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 10 ml DMF were treated with 7.11 g (100 mmol)N-allylmethylamine at 50° C. for 4 h. The solution was concentrated invacuo and the residue was redissolved in ether and water. 2M NaOH wasadded and the inorganic phase was extracted with ether. The combinedorganic phases were washed with water, dried over Na₂SO₄ and evaporated.Column chromatography with a gradient of CH₂Cl₂/MeOH 19:1 to 9:1 yielded7.4 g (85%)5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester as colorless oil, MS: 361 (MH⁺).

7.3

In analogy to example 7.2,5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl esterand methoxyethyl-ethylamine were converted to yield5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester as colorless oil, MS: 379 (MH⁺).

7.4

In analogy to example 7.2,5-(4-Bromo-butoxy)-2,3-dihydro-indole-1-carboxylic acid tert-butyl esterand ethylaminoethanol were converted to yield5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester as yellow oil, MS: 379 (MH⁺).

7.5

To 7.3 g (20.2 mmol)5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 15 ml CH₂Cl₂ 10 ml trifluoroacetic acid were addedat 0° C. The mixture was stirred at reflux for 3 h and was concentratedin vacuo. Water and 2M NaOH were added and the inorganic phase wasextracted with ether. The combined organic phases were washed with waterand dried over Na₂SO₄. Evaporation yielded 5.2 g (98%)Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine as orangeoil, MS: 261 (MH⁺).

7.6

In analogy to example 7.5,5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester was converted to yield[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-(2-methoxy-ethyl)-methyl-amineas light brown oil, MS: 279 (MH⁺).

7.7

In analogy to example 7.5,5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester was converted to yield2-{[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-ethyl-amino}-ethanol aslight yellow oil, MS: 279 (MH⁺).

7.8

220 mg (0.8 mmol)[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-(2-methoxy-ethyl)-methyl-aminein 0.5 ml dioxane were treated with 186 mg (0.9 mmol) chloro-thioformicacid (4-chloro-phenyl)ester in 0.5 ml dioxane at 0° C. The solution wasstirred at RT for 3 h, was diluted with water and ether and a saturatedaqueous solution of NaHCO₃ was added. The inorganic layer was extractedwith ether, washed with water and dried over Na₂SO₄. Columnchromatography with CH₂Cl₂/MeOH 19:1 yielded 230 mg (64%)5-{4-[(2-Methoxy-ethyl)-methyl-amino]-butoxy}-2,3-dihydro-indole-1-carbothioicacid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH⁺, 1Cl).

7.9

In analogy to example 7.8,2-{[4-(2,3-Dihydro-1H-indol-5-yloxy)-butyl]-ethyl-amino}-ethanol andchloro-thioformic acid (4-chloro-phenyl)ester were converted to yield5-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-2,3-dihydro-indole-1-carbothioicacid O-(4-chloro-phenyl)ester as yellow viscous oil, MS: 449 (MH⁺, 1Cl).

7.10

In analogy to example 7.8,Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine andchloro-thioformic acid (4-chloro-phenyl)ester were converted to yield5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acidO-(4-chloro-phenyl)ester as light grey waxy solid, MS: 431 (MH⁺, 1Cl).

7.11

In analogy to example 7.8,Allyl-[4-(2,3-dihydro-1H-indol-5-yloxy)-butyl]-methyl-amine andchloro-thioformic acid (4-chloro-phenyl)ester were converted to yield5-[4-(Allyl-methyl-amino)-butoxy]-2,3-dihydro-indole-1-carbothioic acidO-(4-fluoro-phenyl)ester as light yellow viscous oil, MS: 415 (MH⁺).

Example 8

8.1

4 g (20 mmol) 5-bromo-indoline in 50 ml CH₂Cl₂ were treated with 4.4 g(20 mmol) di.-tert.-butyldicarbonate at RT over night. The reactionmixture was concentrated in vacuo and triturated with hexane to yield5.3 g (89%) 5-Bromo-2,3-dihydro-indole-1-carboxylic acid tert-butylester as colorless solid, MS: 297 (M, 1Br).

8.2

To 3.73 g (12.5 mmol) 5-Bromo-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 25 ml piperidine 722 mg (0.63 mmol)tetrakis-(triphenylphosphine)-palladium and 120 mg (0.625 mmol) CuI wereadded. The solution was purged with argon and was heated to 80° C. overa period of 45 min, during which 0.9 ml (9.4 mmol) 4-pentynol wereadded. Additional 0.9 ml (9.4 mmol) 4-pentynol were added and themixture was stirred for 2 h, poured into ice water and 2M HCl was added.The inorganic phase was extracted with ether, the combined organicphases were washed with water and dried over Na₂SO₄. Purification onsilica gel with hexane/EtOAc 4:1 to 2:1 yielded 3.0 g (79%)5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester as light brown solid, MS: 302 (MH⁺). (See also: Stara,Irena G.; Stary, Ivo; Kollarovic, Adrian; Teply, Filip; Saman, David;Fiedler, Pavel. Coupling reactions of halobenzenes with alkynes. Thesynthesis of phenylacetylenes and symmetrical or unsymmetrical1,2-diphenylacetylenes. Collect. Czech. Chem. Commun. (1999), 64(4),649–672)

8.3

2.8 g (9.3 mmol)5-(5-Hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 60 ml MeOH were subjected to hydrogenation with 10%Pd/C to yield 2.8 g (quantitative)5-(5-Hydroxy-pentyl)-2,3-dihydro-indole-1-carboxylic acid tert-butylester as colorless viscous oil, MS: 305 (M).

8.4

To 2.75 g (9 mmol) 5-(5-Hydroxy-pentyl)-2,3-dihydro-indole-1-carboxylicacid tert-butyl ester in 100 ml CH₂Cl₂, 0.87 ml (11 mmol)methanesulfonyl chloride and 3.8 ml (27 mmol) triethylamine were addedat 0° C. The solution was concentrated in vacuo to yield crude5-(5-Methanesulfonyloxy-pentyl)-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester as yellow viscous oil, MS: 384 (MH⁺). The crudematerial was dissolved in 5 ml DMF and 5 ml (50 mmol)N-allylmethylamine. The mixture was heated to 80° C. for 3 h,concentrated and the residue was dissolved in water and ether, 2M NaOHwas added and the inorganic phase was extacted with ether. The combinedorganic phases were washed with water and dried over Na₂SO₄. Columnchromatography on silica gel with CH₂Cl₂:MeOH 9:1 yielded 2.5 g (72%)5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester as colorless liquid, MS: 359 (MH⁺).

8.5

2.45 g (6.8 mmol)5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acidtert-butyl ester in 5 ml CH₂Cl₂ were treated with 4 ml TFA at 0° C. Thesolution was stirred at RT for 0.5 h, and at 40° C. for 1 h. Thesolution was concentrated and the residue was dissolved in ether andwater. 2M NaOH was added and the inorganic phase was extracted withether. The combined organic phases were washed with water and dried overNa₂SO₄ to yield 1.65 g (94%)Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine as lightyellow oil, MS: 259 (MH⁺).

8.6

To 130 mg (0.5 mmol)Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 2 ml CH₂Cl₂0.34 ml (2 mmol) Huenig's base were added, followed by 0.28 ml (2 mmol)4-chlorophenyl chloroformate. The solution was stirred at RT for 30 min,was concentrated and dissolved in 0.1 M NaOH and ether. The inorganicphase was extracted with ether. The combined organic phases were washedwith water and dried over Na₂SO₄. Column chromatography on silica gelwith CH₂Cl₂/MeOH 9:1 yielded 160 mg (77%)5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylic acid4-chloro-phenyl ester as light yellow oil, MS: 413 (MH⁺, 1Cl).

8.7

130 mg (0.5 mmol)Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 0.5 mldioxane were treated with 0.072 ml (0.5 mmol)chlorothio-formicacid-O-(4-chlorophenyl)-ester at 15° C. The mixture wasstirred for 15 min, concentrated and purified by column chromatographyon silica gel with a gradient of CH₂Cl₂/MeOH 99:1 to 97:3 to yield 92 mg5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acidO-(4-chloro-phenyl)ester as colorless oil. The corresponding acetic acidsalt was prepared by treatment with acetic acid in CH₂Cl₂ to yield 101mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioicacid O-(4-chloro-phenyl)ester-acetic acid as light brown viscous oil,MS: 429 (MH⁺, 1Cl).

Example 9

A solution of 0.153 mmol of the corresponding amine in 0.35 ml drydioxane was treated with 0.23 mmol of the corresponding isocyanate in0.54 ml dry dioxane. The solution was allowed to stand at roomtemperature over night. The resulting reaction mixture was treated with0.15 ml formic acid and purified by preparative HPLC [RP-18,acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95% acetonitrile].After evaporation the resulting compound was obtained as amino formate.

MS No. Compound MH⁺ Amine Isocyanate 9.1 5-[4-(Allyl-methyl-amino)- 416Allyl-[4-(2,3- 2,4 Difluorophenyl- butoxy]-2,3-dihydro-dihydro-1H-indol- isocyanate indole-1-carboxylic acid 5-yloxy)-butyl]-(2,4-difluoro-phenyl)-amide methyl-amine 9.2 5-[4-(Allyl-methyl-amino)-398 Allyl-[4-(2,3- 4-Fluorophenyl- butoxy]-2,3-dihydro-dihydro-1H-indol- isocyanate indole-1-carboxylic acid (4-5-yloxy)-butyl]- fluoro-phenyl)-amide methyl-amine 9.35-[4-(Allyl-methyl-amino)- 394 Allyl-[4-(2,3- 4-Methylphenyl-butoxy]-2,3-dihydro- dihydro-1H-indol- isocyanate indole-1-carboxylicacid p- 5-yloxy)-butyl]- tolylamide methyl-amine 9.45-[4-(Allyl-methyl-amino)- 458 Allyl-[4-(2,3- 4-Bromophenyl-butoxy]-2,3-dihydro- (1 Br) dihydro-1H-indol- isocyanateindole-1-carboxylic acid (4- 5-yloxy)-butyl]- bromo-phenyl)-amidemethyl-amine 9.5 5-[4-(Allyl-methyl-amino)- 440 Allyl-[4-(2,3-2,4-Dimethoxy- butoxy]-2,3-dihydro- dihydro-1H-indol- phenyl-isocyanateindole-1-carboxylic acid 5-yloxy)-butyl]- (2,4-dimethoxy-phenyl)-methyl-amine amide 9.6 5-[4-(Allyl-methyl-amino)- 410 Allyl-[4-(2,3-4-Methoxyphenyl- butoxy]-2,3-dihydro- dihydro-1H-indol- isocyanateindole-1-carboxylic acid (4- 5-yloxy)-butyl]- methoxy-phenyl)-amidemethyl-amine 9.7 5-[4-(Allyl-methyl-amino)- 430 Allyl-[4-(2,3-2-Naphthylphenyl- butoxy]-2,3-dihydro- dihydro-1H-indol- isocyanateindole-1-carboxylic acid 5-yloxy)-butyl]- naphthalen-2-ylamidemethyl-amine 9.8 5-[4-(Allyl-methyl-amino)- 422 Allyl-[4-(2,3-4-Acetylphenyl- butoxy]-2,3-dihydro- dihydro-1H-indol- isocyanateindole-1-carboxylic acid (4- 5-yloxy)-butyl]- acetyl-phenyl)-amidemethyl-amine 9.9 5-[5-(Allyl-methyl-amino)- 414 Allyl-[5-(2,3-2,4-Difluorophenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol-isocyanate 1-carboxylic acid (2,4- 5-yl)-pentyl]- difluoro-phenyl)-amidemethyl-amine 9.10 5-[5-(Allyl-methyl-amino)- 396 Allyl-[5-(2,3-4-Fluorophenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol- isocyanate1-carboxylic acid (4-fluoro- 5-yl)-pentyl]- phenyl)-amide methyl-amine9.11 5-[5-(Allyl-methyl-amino)- 392 Allyl-[5-(2,3- 4-Methylphenyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- isocyanate 1-carboxylicacid p- 5-yl)-pentyl]- tolylamide methyl-amine 9.125-[5-(Allyl-methyl-amino)- 456 Allyl-[5-(2,3- 4-Bromophenyl-pentyl]-2,3-dihydro-indole- (1 Br) dihydro-1H-indol- isocyanate1-carboxylic acid (4-bromo- 5-yl)-pentyl]- phenyl)-amide methyl-amine9.13 5-[5-(Allyl-methyl-amino)- 438 Allyl-[5-(2,3- 2,4-Dimethoxy-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- phenyl-isocyanate1-carboxylic acid (2,4- 5-yl)-pentyl]- dimethoxy-phenyl)-amidemethyl-amine 9.14 5-[5-(Allyl-methyl-amino)- 408 Allyl-[5-(2,3-4-Methoxyphenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol-isocyanate 1-carboxylic acid (4- 5-yl)-pentyl]- methoxy-phenyl)-amidemethyl-amine 9.15 5-[5-(Allyl-methyl-amino)- 428 Allyl-[5-(2,3-2-Naphthylphenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol-isocyanate 1-carboxylic acid 5-yl)-pentyl]- naphthalen-2-ylamidemethyl-amine 9.16 5-[5-(Allyl-methyl-amino)- 420 Allyl-[5-(2,3-4-Acetylphenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol- isocyanate1-carboxylic acid (4-acetyl- 5-yl)-pentyl]- phenyl)-amide methyl-amine9.17 6-[4-(Allyl-methyl-amino)- 434 Allyl-methyl-[4- 4-Acetylphenyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- isocyanatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid (4-acetyl-but-2-enyl]-amine phenyl)-amide 9.18 6-[4-(Allyl-methyl-amino)- 422.3Allyl-methyl-[4- 4-Methoxyphenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- isocyanate dihydro-2H-quinoline-1-quinolin-6-yloxy)- carboxylic acid (4-methoxy- but-2-enyl]-aminephenyl)-amide 9.19 6-[4-(Allyl-methyl-amino)- 406.3 Allyl-methyl-[4-P-Tolyl-isocyanate but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid p-tolylamidebut-2-enyl]-amine 9.20 6-[4-(Allyl-methyl-amino)- 442.3 Allyl-methyl-[4-1-Naphthyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- isocyanatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid naphthalen-but-2-enyl]-amine 1-ylamide 9.21 6-[4-(Allyl-methyl-amino)- 428.3Allyl-methyl-[4- 2,4-Difluorophenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- isocyanate dihydro-2H-quinoline-1-quinolin-6-yloxy)- carboxylic acid (2,4- but-2-enyl]-aminedifluoro-phenyl)-amide 9.22 6-[4-(Allyl-methyl-amino)- 478.2Allyl-methyl-[4- 4-Fluoro-3- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-Trifluoromethyl- dihydro-2H-quinoline-1- quinolin-6-yloxy)-Phenyl-isocyanate carboxylic acid (4-fluoro-3- but-2-enyl]-aminetrifluoromethyl-phenyl)- amide 9.23 6-[4-(Allyl-methyl-amino)- 410.2Allyl-methyl-[4- 4-Fluorophenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- isocyanate dihydro-2H-quinoline-1-quinolin-6-yloxy)- carboxylic acid (4-fluoro- but-2-enyl]-aminephenyl)-amide 9.24 6-[4-(Allyl-methyl-amino)- 452.3 Allyl-methyl-[4-2,4-Dimethoxy- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-phenyl-isocyanate dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylicacid (2,4- but-2-enyl]-amine dimethoxy-phenyl)-amide 9.256-[4-(Allyl-methyl-amino)- 438.3 Allyl-methyl-[4- 4-(Methylthio)-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- phenyl-isocyanatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid (4-but-2-enyl]-amine methylsulfanyl-phenyl)- amide 9.266-[4-(Allyl-methyl-amino)- 470.1 Allyl-methyl-[4- 4-Bromophenyl-but-2-enyloxy]-3,4- (1 Br) (1,2,3,4-tetrahydro- isocyanatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid (4-bromo-but-2-enyl]-amine phenyl)-amide 9.27 6-[4-(Allyl-methyl-amino)- 406.3Allyl-methyl-[4- Benzyl-isocyanate but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- dihydro-2H-quinoline-1- quinolin-6-yloxy)-carboxylic acid benzylamide but-2-enyl]-amine 9.286-[4-(Allyl-methyl-amino)- 448.2 Allyl-methyl-[4- 4-N-Butylphenyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- isocyanatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid (4-butyl-but-2-enyl]-amine phenyl)-amide 9.29 6-[4-(Allyl-methyl-amino)- 420Allyl-methyl-[4- Phenethyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-isocyanate dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acidphenethyl- but-2-enyl]-amine amide 9.30 6-[6-(Allyl-methyl-amino)- 436Allyl-methyl-[6- 4-Tolyl-isocyanate hexyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- quinoline-1-carboxylic acid quinolin-6-yloxy)-p-tolylamide hexyl]-amine 9.31 6-[6-(Allyl-methyl-amino)- 440Allyl-methyl-[6- 4-Fluorophenyl- hexyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- isocyanate quinoline-1-carboxylic acidquinolin-6-yloxy)- (4-fluoro-phenyl)-amide hexyl]-amine 9.326-[6-(Allyl-methyl-amino)- 500 Allyl-methyl-[6- 4-Bromophenyl-hexyloxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro- isocyanatequinoline-1-carboxylic acid quinolin-6-yloxy)- (4-bromo-phenyl)-amidehexyl]-amine 9.33 6-[6-(Allyl-methyl-amino)- 478 Allyl-methyl-[6-4-Butylphenyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isocyanatequinoline-1-carboxylic acid quinolin-6-yloxy)- (4-butyl-phenyl)-amidehexyl]-amine 9.34 6-[4-(Allyl-methyl-amino)- 430 Allyl-methyl-[4-2,4-Difluorophenyl- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-isocyanate quinoline-1-carboxylic acid quinolin-6-yloxy)-(2,4-difluoro-phenyl)-amide butyl]-amine 9.35 6-[4-(Allyl-methyl-amino)-412 Allyl-methyl-[4- 4-Fluorophenyl- butoxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- isocyanate quinoline-1-carboxylic acidquinolin-6-yloxy)- (4-fluoro-phenyl)-amide butyl]-amine 9.366-[4-(Allyl-methyl-amino)- 408 Allyl-methyl-[4- 4-Methylphenyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isocyanatequinoline-1-carboxylic acid quinolin-6-yloxy)- p-tolylamide butyl]-amine9.37 6-[4-(Allyl-methyl-amino)- 472 Allyl-methyl-[4- 4-Bromophenyl-butoxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro- isocyanatequinoline-1-carboxylic acid quinolin-6-yloxy)- (4-bromo-phenyl)-amidebutyl]-amine 9.38 6-[4-(Allyl-methyl-amino)- 454 Allyl-methyl-[4-2,4-Dimethoxy- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-phenyl-isocyanate quinoline-1-carboxylic acid quinolin-6-yloxy)-(2,4-dimethoxy-phenyl)- butyl]-amine amide 9.396-[4-(Allyl-methyl-amino)- 424 Allyl-methyl-[4- 4-Methoxyphenyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isocyanatequinoline-1-carboxylic acid quinolin-6-yloxy)- (4-methoxy-phenyl)-amidebutyl]-amine 9.40 6-[4-(Allyl-methyl-amino)- 444 Allyl-methyl-[4-2-Naphthylphenyl- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-isocyanate quinoline-1-carboxylic acid quinolin-6-yloxy)-naphthalen-2-ylamide butyl]-amine 9.41 6-[4-(Allyl-methyl-amino)- 436Allyl-methyl-[4- 4-Acetylphenyl- butoxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- isocyanate quinoline-1-carboxylic acidquinolin-6-yloxy)- (4-acetyl-phenyl)-amide butyl]-amine 9.426-(4-Diethylamino-butoxy)- 414 Diethyl-[4-(1,2,3,4- 4-Fluorophenyl-3,4-dihydro-2H-quinoline- tetrahydro- isocyanate 1-carboxylic acid(4-fluoro- quinolin-6-yloxy)- phenyl)-amide butyl]-amine 9.436-(4-Diethylamino-butoxy)- 410 Diethyl-[4-(1,2,3,4- 4-Methylphenyl-3,4-dihydro-2H-quinoline- tetrahydro- isocyanate 1-carboxylic acid p-quinolin-6-yloxy)- tolylamide butyl]-amine 9.446-(4-Diethylamino-butoxy)- 474 Diethyl-[4-(1,2,3,4- 4-Bromophenyl-3,4-dihydro-2H-quinoline- (1 Br) tetrahydro- isocyanate 1-carboxylicacid (4-bromo- quinolin-6-yloxy)- phenyl)-amide butyl]-amine

Example 10

A solution of 0.153 mmol of the corresponding amine in 0.35 ml drydioxane was treated with (0.46 mmol; 3 equivalents) Huenig's base and0.2 mmol of the corresponding chloroformate in 0.54 ml dry dioxane. Thesolution was allowed to stand at room temperature over night and theresulting reaction mixture was treated with 0.15 ml formic acid andpurified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation the resultingcompound was obtained as a mixture of amino hydrochloride and formate.

MS No. Compound MH+ 1. Educt 2. Educt 10.1 6-[4-(allyl-methyl-amino)-438 Allyl-methyl-[4- 4-Nitrophenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- chloroformate dihydro-2H-quinoline-1-quinolin-6-yloxy)- carboxylic acid 4-nitro- but-2-enyl]-amine phenylester 10.2 6-[4-(Allyl-methyl-amino)- 401 Allyl-methyl-[4- Hexyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- chloroformatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid hexyl esterbut-2-enyl]-amine 10.3 6-[4-(Allyl-methyl-amino)- 471 Allyl-methyl-[4-4-Bromophenyl- but-2-enyloxy]-3,4- (1 Br) (1,2,3,4-tetrahydro-chloroformate dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid4-bromo- but-2-enyl]-amine phenyl ester 10.4 6-[4-(Allyl-methyl-amino)-373 Allyl-methyl-[4- Isobutyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-chloroformate dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acidisobutyl but-2-enyl]-amine ester 10.5 6-[4-(Allyl-methyl-amino)- 393Allyl-methyl-[4- Phenyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-chloroformate dihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acidphenyl ester but-2-enyl]-amine 10.6 6-[4-(Allyl-methyl-amino)- 423Allyl-methyl-[4- 4-Methoxyphenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- chloroformate dihydro-2H-quinoline-1-quinolin-6-yloxy)- carboxylic acid 4-methoxy- but-2-enyl]-amine phenylester 10.7 6-[4-(Allyl-methyl-amino)- 407 Allyl-methyl-[4- P-Tolyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- chloroformatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid p-tolyl esterbut-2-enyl]-amine 10.8 6-[4-(Allyl-methyl-amino)- 451 Allyl-methyl-[4-4-Methoxy- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- carbonyl-phenyldihydro-2H-quinoline-1- quinolin-6-yloxy)- chloroformate carboxylic acid4- but-2-enyl]-amine methoxycarbonyl-phenyl ester 10.96-[4-(Allyl-methyl-amino)- 373 Allyl-methyl-[4- Butyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- chloroformatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid butyl esterbut-2-enyl]-amine 10.10 6-[4-(Allyl-methyl-amino)- 411 Allyl-methyl-[4-4-Fluorophenyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- chloroformatedihydro-2H-quinoline-1- quinolin-6-yloxy)- carboxylic acid 4-fluoro-but-2-enyl]-amine phenyl ester 10.11 6-[6-(Allyl-methyl-amino)- 501Allyl-methyl-[6- 4-Bromophenyl- hexyloxy]-3,4-dihydro-2H- (1 Br)(1,2,3,4-tetrahydro- chloroformate quinoline-1-carboxylic acidquinolin-6-yloxy)- 4-bromo-phenyl ester hexyl]-amine 10.126-[6-(Allyl-methyl-amino)- 441 Allyl-methyl-[6- 4-Fluorophenyl-hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- chloroformatequinoline-1-carboxylic acid quinolin-6-yloxy)- 4-fluoro-phenyl esterhexyl]-amine 10.13 6-[6-(Allyl-methyl-amino)- 437 Allyl-methyl-[6-4-Toloyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- chloroformatequinoline-1-carboxylic acid quinolin-6-yloxy)- p-tolyl esterhexyl]-amine 10.14 6-[6-(Allyl-methyl-amino)- 431 Allyl-methyl-[6-Hexyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- chloroformatequinoline-1-carboxylic acid quinolin-6-yloxy)- hexyl ester hexyl]-amine10.15 6-[6-(Allyl-methyl-amino)- 453 Allyl-methyl-[6- 4-Methoxyphenyl-hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- chloroformatequinoline-1-carboxylic acid quinolin-6-yloxy)- 4-methoxy-phenyl esterhexyl]-amine

Example 11

A solution of 0.133 mmol of the corresponding amine in 0.5 ml dry DMFwas treated subsequently with 0.17 mmol (1.3 equivalents) of thecorresponding acid, 0.266 mmol (2 equivalents) Huenig's base, 0.266 mmol(2 equivalents) N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride) (EDCI) as well as catalytic amount ofHydroxybenzotriazole (HOBt) (approximately 0.02 mmol). The solution wasallowed to stand at room temperature over night. The resulting reactionmixture was treated with 0.15 ml formic acid and purified by preparativeHPLC [RP-18, acetonitrile (0.1% HCOOH)/water (0.1% HCOOH), 10% to 95%acetonitrile]. After evaporation, the resulting compound was obtained asa mixture of amino hydrochloride and formate.

MS No. Compound MH⁺ Amine Acid 11.1 {5-[4-(Allyl-methyl-amino)- 443Allyl-[4-(2,3- 4-Bromobenzoic butoxy]-2,3-dihydro-indol- (1 Br)dihydro-1H-indol- acid 1-yl}-(4-bromo-phenyl)- 5-yloxy)-butyl]-methanone methyl-amine 11.2 3-{5-[4-(Allyl-methyl- 390 Allyl-[4-(2,3-3-Cyanobenzoic amino)-butoxy]-2,3- dihydro-1H-indol- aciddihydro-indole-1- 5-yloxy)-butyl]- carbonyl}-benzonitrile methyl-amine11.3 {5-[4-(Allyl-methyl-amino)- 383 Allyl-[4-(2,3- 4-Fluorobenzoicbutoxy]-2,3-dihydro-indol- dihydro-1H-indol- acid1-yl}-(4-fluoro-phenyl)- 5-yloxy)-butyl]- methanone methyl-amine 11.4{5-[4-(Allyl-methyl-amino)- 449 Allyl-[4-(2,3- 5-Bromothiophene-butoxy]-2,3-dihydro-indol- (1 Br) dihydro-1H-indol- 2-carboxylic acid1-yl}-(5-bromo-thiophen-2- 5-yloxy)-butyl]- yl)-methanone methyl-amine11.5 {5-[4-(Allyl-methyl-amino)- 399 Allyl-[4-(2,3- 4-Chloro-benzoicbutoxy]-2,3-dihydro-indol- (1 Cl) dihydro-1H-indol- acid1-yl}-(4-chloro-phenyl)- 5-yloxy)-butyl]- methanone methyl-amine 11.6{5-[4-(Allyl-methyl-amino)- 365 Allyl-[4-(2,3- Benzoic acidbutoxy]-2,3-dihydro-indol- dihydro-1H-indol- 1-yl}-phenyl-methanone5-yloxy)-butyl]- methyl-amine 11.7 {5-[4-(Allyl-methyl-amino)- 433Allyl-[4-(2,3- 4-Trifluoromethyl butoxy]-2,3-dihydro-indol-dihydro-1H-indol- benzoic acid 1-yl}-(4-trifluoromethyl-5-yloxy)-butyl]- phenyl)-methanone methyl-amine 11.8{5-[5-(Allyl-methyl-amino)- 441 Allyl-[5-(2,3- 4-Bromobenzoicpentyl]-2,3-dihydro-indol- (1 Br) dihydro-1H-indol- acid1-yl}-(4-bromo-phenyl)- 5-yl)-pentyl]- methanone methyl-amine 11.93-{5-[5-(Allyl-methyl- 388 Allyl-[5-(2,3- 3-Cyanobenzoicamino)-pentyl]-2,3- dihydro-1H-indol- acid dihydro-indole-1-5-yl)-pentyl]- carbonyl}-benzonitrile methyl-amine 11.10{5-[5-(Allyl-methyl-amino)- 381 Allyl-[5-(2,3- 4-Fluorobenzoicpentyl]-2,3-dihydro-indol- dihydro-1H-indol- acid1-yl}-(4-fluoro-phenyl)- 5-yl)-pentyl]- methanone methyl-amine 11.11{5-[5-(Allyl-methyl-amino)- 447 Allyl-[5-(2,3- 5-Bromothiophene-pentyl]-2,3-dihydro-indol- (1 Br) dihydro-1H-indol- 2-carboxylic acid1-yl}-(5-bromo-thiophen-2- 5-yl)-pentyl]- yl)-methanone methyl-amine11.12 {5-[5-(Allyl-methyl-amino)- 397 Allyl-[5-(2,3- 4-Chlorobenzoicpentyl]-2,3-dihydro-indol- (1 Cl) dihydro-1H-indol- acid1-yl}-(4-chloro-phenyl)- 5-yl)-pentyl]- methanone methyl-amine 11.13{5-[5-(Allyl-methyl-amino)- 363 Allyl-[5-(2,3- Benzoic acidpentyl]-2,3-dihydro-indol- dihydro-1H-indol- 1-yl}-phenyl-methanone5-yl)-pentyl]- methyl-amine 11.14 3-{6-[4-(Allyl-methyl- 402Allyl-methyl-[4- 3-Cyanobenzoic amino)-but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- acid dihydro-2H-quinoline-1- quinolin-6-yloxy)-carbonyl}-benzonitrile but-2-enyl]-amine 11.15{6-[4-(Allyl-methyl-amino)- 455 Allyl-methyl-[4- 4-Bromobenzoicbut-2-enyloxy]-3,4- (1 Br) (1,2,3,4-tetrahydro- aciddihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)- (4-bromo-phenyl)-but-2-enyl]-amine methanone 11.16 1-{6-[4-(Allyl-methyl- 427Allyl-methyl-[4- 2,4-Difluorophenyl amino)-but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- acetic acid dihydro-2H-quinolin-1-yl}-quinolin-6-yloxy)- 2-(2,4-difluoro-phenyl)- but-2-enyl]-amine ethanone11.17 1-(4-{6-[4-(Allyl-methyl- 419 Allyl-methyl-[4- Acetophenone-4-amino)-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- Carboxylic aciddihydro-2H-quinoline-1- quinolin-6-yloxy)- carbonyl}-phenyl)-ethanonebut-2-enyl]-amine 11.18 {6-[4-(Allyl-methyl-amino)- 461 Allyl-methyl-[4-5-Bromothiophene- but-2-enyloxy]-3,4- (1 Br) (1,2,3,4-tetrahydro-2-Carboxylic acid dihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)-(5-bromo-thiophen-2-yl)- but-2-enyl]-amine methanone 11.19{6-[4-(Allyl-methyl-amino)- 411 Allyl-methyl-[4- 3-Chlorobenzoicbut-2-enyloxy]-3,4- (1 Cl) (1,2,3,4-tetrahydro- aciddihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)- (3-chloro-phenyl)-but-2-enyl]-amine methanone 11.20 1-{6-[4-(Allyl-methyl- 409Allyl-methyl-[4- 4-Fluorophenyl amino)-but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- acetic acid dihydro-2H-quinolin-1-yl}-quinolin-6-yloxy)- 2-(4-fluoro-phenyl)- but-2-enyl]-amine ethanone 11.21{6-[4-(Allyl-methyl-amino)- 395 Allyl-methyl-[4- 4-Fluorobenzoicbut-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- acid dihydro-2H-quinolin-1-yl}-quinolin-6-yloxy)- (4-fluoro-phenyl)- but-2-enyl]-amine methanone 11.22{6-[4-(Allyl-methyl-amino)- 411 Allyl-methyl-[4- 4-Chlorobenzoicbut-2-enyloxy]-3,4- (1 Cl) (1,2,3,4-tetrahydro- aciddihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)- (4-chloro-phenyl)-but-2-enyl]-amine methanone 11.23 {6-[4-(Allyl-methyl-amino)- 445Allyl-methyl-[4- 4-(Trifluoromethyl) but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- Benzoic acid dihydro-2H-quinolin-1-yl}-quinolin-6-yloxy)- (4-trifluoromethyl-phenyl)- but-2-enyl]-aminemethanone 11.24 {6-[4-(Allyl-methyl-amino)- 378 Allyl-methyl-[4-Nicotinic acid but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-dihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)- pyridin-3-yl-methanonebut-2-enyl]-amine 11.25 {6-[4-(Allyl-methyl-amino)- 409 Allyl-methyl-[4-4-Fluoro-3-Methyl but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- benzoic aciddihydro-2H-quinolin-1-yl}- quinolin-6-yloxy)-(4-fluoro-3-methyl-phenyl)- but-2-enyl]-amine methanone 11.263-{6-[6-(Allyl-methyl- 432 Allyl-methyl-[6- 3-Cyanophenylamino)-hexyloxy]-3,4- (1,2,3,4-tetrahydro- benoicaciddihydro-2H-quinoline-1- quinolin-6-yloxy)- carbonyl}-benzonitrilehexyl]-amine 11.27 {6-[6-(Allyl-methyl-amino)- 485 Allyl-methyl-[6-4-Bromophenyl hexyloxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro-benzoicacid quinolin-1-yl}-(4-bromo- quinolin-6-yloxy)-phenyl)-methanone hexyl]-amine 11.28 {6-[6-(Allyl-methyl-amino)- 491Allyl-methyl-[6- 2-Bromothiophene- hexyloxy]-3,4-dihydro-2H- (1 Br)(1,2,3,4-tetrahydro- 5-carboxylicacid quinolin-1-yl}-(5-bromo-quinolin-6-yloxy)- thiophen-2-yl)-methanone hexyl]-amine 11.29{6-[6-(Allyl-methyl-amino)- 425 Allyl-methyl-[6- 4-Fluorophenylhexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- benzoic acidquinolin-1-yl}-(4-fluoro- quinolin-6-yloxy)- phenyl)-methanonehexyl]-amine 11.30 {6-[4-(Allyl-methyl-amino)- 457 Allyl-methyl-[4-4-Bromobenzoic butoxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro- acidquinolin-1-yl}-(4-bromo- quinolin-6-yloxy)- phenyl)-methanonebutyl]-amine 11.31 3-{6-[4-(Allyl-methyl- 404 Allyl-methyl-[4-3-Cyanobenzoic amino)-butoxy]-3,4- (1,2,3,4-tetrahydro- aciddihydro-2H-quinoline-1- quinolin-6-yloxy)- carbonyl}-benzonitrilebutyl]-amine 11.32 {6-[4-(Allyl-methyl-amino)- 397 Allyl-methyl-[4-4-Fluorobenzoic butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- acidquinolin-1-yl}-(4-fluoro- quinolin-6-yloxy)- phenyl)-methanonebutyl]-amine 11.33 {6-[4-(Allyl-methyl-amino)- 463 Allyl-methyl-[4-5-Bromothiophene- butoxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro-2-carboxylicacid quinolin-1-yl}-(5-bromo- quinolin-6-yloxy)-thiophen-2-yl)-methanone butyl]-amine 11.34 {6-[4-(Allyl-methyl-amino)-413 Allyl-methyl-[4- 4-Chlorobenzoic butoxy]-3,4-dihydro-2H- (1 Cl)(1,2,3,4-tetrahydro- acid quinolin-1-yl}-(4-chloro- quinolin-6-yloxy)-phenyl)-methanone butyl]-amine 11.35 {6-[4-(Allyl-methyl-amino)- 379Allyl-methyl-[4- Benzoic acid butoxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- quinolin-1-yl}-phenyl- quinolin-6-yloxy)- methanonebutyl]-amine 11.36 {6-[4-(Allyl-methyl-amino)- 447 Allyl-methyl-[4-4-Trifluoromethyl butoxy]-3,4-dihydro- 2H- (1,2,3,4-tetrahydro- benzoicacid quinolin-1-yl}-(4- quinolin-6-yloxy)- trifluoromethyl-phenyl)-butyl]-amine methanone 11.37 (4-Bromo-phenyl)-[6-(4- 459Diethyl-[4-(1,2,3,4- 4-Bromobenzoic diethylamino-butoxy)-3,4- (1 Br)tetrahydro- acid dihydro-2H-quinolin-1-yl]- quinolin-6-yloxy)- methanonebutyl]-amine 11.38 3-[6-(4-Diethylamino- 406 Diethyl-[4-(1,2,3,4-3-Cyanobenzoic butoxy)-3,4-dihydro-2H- tetrahydro- acidquinoline-1-carbonyl]- quinolin-6-yloxy)- benzonitrile butyl]-amine11.39 [6-(4-Diethylamino- 399 Diethyl-[4-(1,2,3,4- 4-Fluorobenzoicbutoxy)-3,4-dihydro-2H- tetrahydro- acid quinolin-1-yl]-(4-fluoro-quinolin-6-yloxy)- phenyl)-methanone butyl]-amine 11.40(5-Bromo-thiophen-2-yl)- 465 Diethyl-[4-(1,2,3,4- 5-Bromothiophene-[6-(4-diethylamino- (1 Br) tetrahydro- 2-carboxylic acidbutoxy)-3,4-dihydro-2H- quinolin-6-yloxy)- quinolin-1-yl]-methanonebutyl]-amine

Example 12

A solution of 0.133 mmol of the corresponding amine was treated with0.17 mmol (1.3 equivalents) of the corresponding isothiocyanate in 0.35ml dry dioxane. The solution was allowed to stand at room temperatureover night, was treated with 0.15 ml formic acid and purified bypreparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water (0.1% HCOOH),10% to 95% acetonitrile]. After evaporation of the correspondingfraction, the compound was obtained as amino formate.

MS No. Compound MH⁺ Amine Isothiocyanate 12.1 5-[4-(Allyl-methyl-amino)-430 Allyl-[4-(2,3- 4-Chlorophenyl- butoxy]-2,3-dihydro- (1 Cl)dihydro-1H-indol- isothiocyanate indole-1-carbothioic acid5-yloxy)-butyl]- (4-chloro-phenyl)-amide methyl-amine 12.25-[4-(Allyl-methyl-amino)- 416 Allyl-[4-(2,3- Cycloheptyl-butoxy]-2,3-dihydro- dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 5-yloxy)-butyl]- cycloheptylamide methyl-amine12.3 5-[4-(Allyl-methyl-amino)- 416 Allyl-[4-(2,3- Cyclohexane-butoxy]-2,3-dihydro- dihydro-1H-indol- methyl- indole-1-carbothioic acid5-yloxy)-butyl]- isothiocyanate cyclohexylmethyl-amide methyl-amine 12.45-[4-(Allyl-methyl-amino)- 444 Allyl-[4-(2,3- 4-Chlorobenzyl-butoxy]-2,3-dihydro- (1 Cl) dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 4- 5-yloxy)-butyl]- chloro-benzylamidemethyl-amine 12.5 5-[4-(Allyl-methyl-amino)- 464 Allyl-[4-(2,3-4-Trifluoromethyl- butoxy]-2,3-dihydro- dihydro-1H-indol- phenyl-indole-1-carbothioic acid 5-yloxy)-butyl]- isothiocyanate(4-trifluoromethyl-phenyl)- methyl-amine amide 12.65-[4-(Allyl-methyl-amino)- 428 Allyl-[4-(2,3- 4-Fluorobenzyl-butoxy]-2,3-dihydro- dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 4- 5-yloxy)-butyl]- fluoro-benzylamidemethyl-amine 12.7 5-[4-(Allyl-methyl-amino)- 410 Allyl-[4-(2,3- Benzyl-butoxy]-2,3-dihydro- dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 5-yloxy)-butyl]- benzylamide methyl-amine 12.85-[4-(Allyl-methyl-amino)- 402 Allyl-[4-(2,3- Cyclohexyl-butoxy]-2,3-dihydro- dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 5-yloxy)-butyl]- cyclohexylamide methyl-amine12.9 5-[5-(Allyl-methyl-amino)- 428 Allyl-[5-(2,3- 4-Chlorophenyl-pentyl]-2,3-dihydro-indole- (1 Cl) dihydro-1H-indol- isothiocyanate1-carbothioic acid (4- 5-yl)-pentyl]- chloro-phenyl)-amide methyl-amine12.10 5-[5-(Allyl-methyl-amino)- 414 Allyl-[5-(2,3- Cycloheptyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- isothiocyanate1-carbothioic acid 5-yl)-pentyl]- cycloheptylamide methyl-amine 12.115-[5-(Allyl-methyl-amino)- 414 Allyl-[5-(2,3- Cyclohexanemethyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- isothiocyanate1-carbothioic acid 5-yl)-pentyl]- cyclohexylmethyl-amide methyl-amine12.12 5-[5-(Allyl-methyl-amino)- 442 Allyl-[5-(2,3- 4-Chlorobenzyl-pentyl]-2,3-dihydro-indole- (1 Cl) dihydro-1H-indol- isothiocyasnate1-carbothioic acid 4-chloro- 5-yl)-pentyl]- benzylamide methyl-amine12.13 5-[5-(Allyl-methyl-amino)- 462 Allyl-[5-(2,3- 4-Trifluoromethyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- phenyl- 1-carbothioic acid(4- 5-yl)-pentyl]- isothiocyanate trifluoromethyl-phenyl)- methyl-amineamide 12.14 5-[5-(Allyl-methyl-amino)- 426 Allyl-[5-(2,3-4-Fluorobenzyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol-isothiocyanate 1-carbothioic acid 4-fluoro- 5-yl)-pentyl]- benzylamidemethyl-amine 12.15 5-[4-(Allyl-methyl-amino)- 390 Allyl-[4-(2,3-1-Isothiocyanato-3- butoxy]-2,3-dihydro- dihydro-1H-indol- methyl-butaneindole-1-carbothioic acid 5-yloxy)-butyl]- (3-methyl-butyl)-amidemethyl-amine 12.16 5-[4-(Allyl-methyl-amino)- 400 Allyl-[4-(2,3-2-Furfuryl- butoxy]-2,3-dihydro- dihydro-1H-indol- isothiocyanateindole-1-carbothioic acid 5-yloxy)-butyl]- (furan-2-ylmethyl)-amidemethyl-amine 12.17 5-[4-(Allyl-methyl-amino)- 348 Allyl-[4-(2,3-Isothiocyanato- butoxy]-2,3-dihydro- dihydro-1H-indol- ethaneindole-1-carbothioic acid 5-yloxy)-butyl]- ethylamide methyl-amine 12.185-[4-(Allyl-methyl-amino)- 376 Allyl-[4-(2,3- Isothiocyanato-butoxy]-2,3-dihydro- dihydro-1H-indol- butane indole-1-carbothioic acid5-yloxy)-butyl]- butylamide methyl-amine 12.195-[4-(Allyl-methyl-amino)- 390 Allyl-[4-(2,3- 1-Isothiocyanato-2-butoxy]-2,3-dihydro- dihydro-1H-indol- methyl-butaneindole-1-carbothioic acid 5-yloxy)-butyl]- (2-methyl-butyl)-amidemethyl-amine 12.20 5-[4-(Allyl-methyl-amino)- 378 Allyl-[4-(2,3-1-Isothiocyanato-2- butoxy]-2,3-dihydro- dihydro-1H-indol-methoxy-ethane indole-1-carbothioic acid 5-yloxy)-butyl]-(2-methoxy-ethyl)-amide methyl-amine 12.21 5-[4-(Allyl-methyl-amino)-452 Allyl-[4-(2,3- 1-Butyl-4- butoxy]-2,3-dihydro- dihydro-1H-indol-isothiocyanato- indole-1-carbothioic acid 5-yloxy)-butyl]- benzene(4-butyl-phenyl)-amide methyl-amine 12.22 5-[4-(Allyl-methyl-amino)- 404Allyl-[4-(2,3- 2-Tetrahydro- butoxy]-2,3-dihydro- dihydro-1H-indol-furfuryl- indole-1-carbothioic acid 5-yloxy)-butyl]- isothiocyanate(tetrahydro-furan-2- methyl-amine ylmethyl)-amide 12.236-[4-(Allyl-methyl-amino)- 444 Allyl-methyl-[4- 4-Chlorophenyl-butoxy]-3,4-dihydro-2H- (1 Cl) (1,2,3,4-tetrahydro- isothiocyanatquinoline-1-carbothioic quinolin-6-yloxy)- acid (4-chloro-phenyl)-butyl]-amine amide 12.24 6-[4-(Allyl-methyl-amino)- 430 Allyl-methyl-[4-Cycloheptyl- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isothiocyanatquinoline-1-carbothioic quinolin-6-yloxy)- acid cycloheptylamidebutyl]-amine 12.25 6-[4-(Allyl-methyl-amino)- 430 Allyl-methyl-[4-Cyclohexane- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- methyl-quinoline-1-carbothioic quinolin-6-yloxy)- isothiocyanate acidcyclohexylmethyl- butyl]-amine amide 12.26 6-[4-(Allyl-methyl-amino)-458 Allyl-methyl-[4- 4-Chlorobenzyl- butoxy]-3,4-dihydro-2H- (1 Cl)(1,2,3,4-tetrahydro- isothiocyasnate quinoline-1-carbothioicquinolin-6-yloxy)- acid 4-chloro-benzylamide butyl]-amine 12.276-[4-(Allyl-methyl-amino)- 478 Allyl-methyl-[4- 4-Trifluoromethyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- phenyl-quinoline-1-carbothioic quinolin-6-yloxy)- isothiocyanat acid(4-trifluoromethyl- butyl]-amine phenyl)-amide 12.286-[4-(Allyl-methyl-amino)- 442 Allyl-methyl-[4- 4-Fluorobenzyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isothiocyanatequinoline-1-carbothioic quinolin-6-yloxy)- acid 4-fluoro-benzylamidebutyl]-amine 12.29 6-[4-(Allyl-methyl-amino)- 424 Allyl-methyl-[4-Benzyl- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isothiocyanatequinoline-1-carbothioic quinolin-6-yloxy)- acid benzylamide butyl]-amine12.30 6-[4-(Allyl-methyl-amino)- 416 Allyl-methyl-[4- Cyclohexyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- isothiocyanatequinoline-1-carbothioic quinolin-6-yloxy)- acid cyclohexylamidebutyl]-amine 12.31 6-[6-(Allyl-methyl-amino)- 472 Allyl-methyl-[6-p-Chlorophenyl- hexyloxy]-3,4-dihydro-2H- (1 Cl) (1,2,3,4-tetrahydro-isothiocyanate quinoline-1-carbothioic quinolin-6-yloxy)- acid(4-chloro-phenyl)- hexyl]-amine amide 12.32 6-[6-(Allyl-methyl-amino)-458 Allyl-methyl-[6- Cycloheptyl- hexyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- isothiocyanate quinoline-1-carbothioicquinolin-6-yloxy)- acid cycloheptylamide hexyl]-amine

Example 13

A solution of 0.14 mmol of the corresponding amine in 0.5 ml dry dioxanewas treated with a solution of 0.14 mmol of the correspondingchlorothionoformate in 0.35 ml dry dioxane. The solution was allowed tostand at room temperature over night, treated with 0.15 ml formic acidand purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation of thecorresponding fraction, the compound was obtained as a mixture of aminohydrochloride and formate.

MS Chloro- No. Compound MH⁺ Amine thionoformate 13.15-[5-(Allyl-methyl-amino)- 413 Allyl-[5-(2,3- 4-Fluorophenyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- chloro- 1-carbothioic acidO-(4- 5-yl)-pentyl]- thionoformate fluoro-phenyl) ester methyl-amine13.2 5-[5-(Allyl-methyl-amino)- 395 Allyl-[5-(2,3- Phenyl-chloro-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- thionoformate1-carbothioic acid O-phenyl 5-yl)-pentyl]- ester methyl-amine 13.35-[5-(Allyl-methyl-amino)- 409 Allyl-[5-(2,3- p-Toloyl-chloro-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- thionoformate1-carbothioic acid O-p-tolyl 5-yl)-pentyl]- ester methyl-amine 13.46-(4-Diethylamino-butoxy)- 431 Diethyl-[4-(1,2,3,4- 4-Fluoro-phenyl-3,4-dihydro-2H-quinoline- tetrahydro- chloro- 1-carbothioic acid O-(4-quinolin-6-yloxy)- thionoformate fluoro-phenyl) ester butyl]-amine 13.56-(4-Diethylamino-butoxy)- 447 Diethyl-[4-(1,2,3,4- 4-Chloro-phenyl-3,4-dihydro-2H-quinoline- (1 Cl) tetrahydro- chloro- 1-carbothioic acidO-(4- quinolin-6-yloxy)- thionoformate chloro-phenyl) ester butyl]-amine13.6 6-[4-(Allyl-methyl-amino)- 429 Allyl-methyl-[4- 4-Fluoro-phenyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- chloro-quinoline-1-carbothioic quinolin-6-yloxy)- thionoformate acidO-(4-fluoro-phenyl) butyl]-amine ester 13.7 6-[4-(Allyl-methyl-amino)-445 Allyl-methyl-[4- 4-Chloro-phenyl- butoxy]-3,4-dihydro-2H- (1 Cl)(1,2,3,4-tetrahydro- chloro- quinoline-1-carbothioic quinolin-6-yloxy)-thionoformate acid O-(4-chloro-phenyl) butyl]-amine ester 13.86-[4-(Allyl-methyl-amino)- 411 Allyl-methyl-[4- Phenyl-chloro-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- thionoformatequinoline-1-carbothioic quinolin-6-yloxy)- acid O-phenyl esterbutyl]-amine

Example 14

A solution of 0.135 mmol of the corresponding amine in 0.75 ml drydioxane was treated with 5 equivalents of triethylamine followed by asolution of 0.175 mmol (1.3 equivalente) of the correspondingsulfamoylchloride in 0.25 ml dry dioxane. The suspension was allowed tostand at room temperature over night, treated with 0.15 ml formic acidand purified by preparative HPLC [RP-18, acetonitrile (0.1% HCOOH)/water(0.1% HCOOH), 10% to 95% acetonitrile]. After evaporation of thecorresponding fraction, the resulting compound was obtained as a mixtureof amino hydrochloride and formate.

MS No. Compound MH⁺ Amine Sulfamoylchloride 14.15-[4-(Allyl-methyl-amino)- 450 Allyl-[4-(2,3- 4-Chlorophenyl-butoxy]-2,3-dihydro- (1 Cl) dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid (4- 5-yloxy)-butyl]- chloro-phenyl)-amidemethyl-amine 14.2 5-[4-(Allyl-methyl-amino)- 430 Allyl-[4-(2,3-4-Methylphenyl- butoxy]-2,3-dihydro- dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid p- 5-yloxy)-butyl]- tolylamide methyl-amine 14.35-[4-(Allyl-methyl-amino)- 441 Allyl-[4-(2,3- 4-Cyanophenyl-butoxy]-2,3-dihydro- dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid (4- 5-yloxy)-butyl]- cyano-phenyl)-amidemethyl-amine 14.4 5-[4-(Allyl-methyl-amino)- 446 Allyl-[4-(2,3-4-Methoxyphenyl- butoxy]-2,3-dihydro- dihydro-1H-indol-sulfamoylchloride indole-1-sulfonic acid (4- 5-yloxy)-butyl]-methoxy-phenyl)-amide methyl-amine 14.5 5-[4-(Allyl-methyl-amino)- 452Allyl-[4-(2,3- 3,4-Difluorophenyl- butoxy]-2,3-dihydro-dihydro-1H-indol- sulfamoylchloride indole-1-sulfonic acid (3,4-5-yloxy)-butyl]- difluoro-phenyl)-amide methyl-amine 14.65-[4-(Allyl-methyl-amino)- 434 Allyl-[4-(2,3- 3-Fluorophenyl-butoxy]-2,3-dihydro- dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid (3- 5-yloxy)-butyl]- fluoro-phenyl)-amidemethyl-amine 14.7 5-[4-(Allyl-methyl-amino)- 452 Allyl-[4-(2,3-2,4-Difluorophenyl- butoxy]-2,3-dihydro- dihydro-1H-indol-sulfamoylchloride indole-1-sulfonic acid (2,4- 5-yloxy)-butyl]-difluoro-phenyl)-amide methyl-amine 14.8 5-[4-(Allyl-methyl-amino)- 452Allyl-[4-(2,3- 2,5-Difluorophenyl- butoxy]-2,3-dihydro-dihydro-1H-indol- sulfamoylchloride indole-1-sulfonic acid (2,5-5-yloxy)-butyl]- difluoro-phenyl)-amide methyl-amine 14.95-[4-(Allyl-methyl-amino)- 494 Allyl-[4-(2,3- 4-Bromophenyl-butoxy]-2,3-dihydro- (1 Br) dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid (4- 5-yloxy)-butyl]- bromo-phenyl)-amidemethyl-amine 14.10 5-[4-(Allyl-methyl-amino)- 416 Allyl-[4-(2,3- Phenyl-butoxy]-2,3-dihydro- dihydro-1H-indol- sulfamoylchlorideindole-1-sulfonic acid 5-yloxy)-butyl]- phenylamide methyl-amine 14.115-[5-(Allyl-methyl-amino)- 414 Allyl-[5-(2,3- Phenyl-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- sulfamoylchloride1-sulfonic acid phenylamide 5-yl)-pentyl]- methyl-amine 14.125-[5-(Allyl-methyl-amino)- 448 Allyl-[5-(2,3- 4-Chlorophenyl-pentyl]-2,3-dihydro-indole- (1 Cl) dihydro-1H-indol- sulfamoylchloride1-sulfonic acid (4-chloro- 5-yl)-pentyl]- phenyl)-amide methyl-amine14.13 5-[5-(Allyl-methyl-amino)- 450 Allyl-[5-(2,3- 2,4-pentyl]-2,3-dihydro-indole- dihydro-1H-indol- Difluorophenyl- 1-sulfonicacid (2,4- 5-yl)-pentyl]- sulfamoylchloride difluoro-phenyl)-amidemethyl-amine 14.14 5-[5-(Allyl-methyl-amino)- 432 Allyl-[5-(2,3-4-Fluorophenyl- pentyl]-2,3-dihydro-indole- dihydro-1H-indol-sulfonamylchoride 1-sulfonic acid (4-fluoro- 5-yl)-pentyl]-phenyl)-amide methyl-amine 14.15 6-[4-(Allyl-methyl-amino)- 462Allyl-methyl-[4- 4-Chlorophenyl- but-2-enyloxy]-3,4- (1 Cl)(1,2,3,4-tetrahydro- sulfamoylchloride dihydro-2H-quinoline-1-quinolin-6-yloxy)- sulfonic acid (4-chloro- but-2-enyl]-aminephenyl)-amide 14.16 6-[4-(Allyl-methyl-amino)- 446 Allyl-methyl-[4-4-Fluorophenyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-sulfamoylchloride dihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonicacid (4-fluoro- but-2-enyl]-amine phenyl)-amide 14.176-[4-(Allyl-methyl-amino)- 506 Allyl-methyl-[4- 4-Bromophenyl-but-2-enyloxy]-3,4- (1 Br) (1,2,3,4-tetrahydro- sulfamoylchloridedihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonic acid (4-bromo-but-2-enyl]-amine phenyl)-amide 14.18 6-[4-(Allyl-methyl-amino)- 442Allyl-methyl-[4- p-tolyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-sulfamoylchloride dihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonicacid (p-tolyl)- but-2-enyl]-amine amide 14.19 6-[4-(Allyl-methyl-amino)-464 Allyl-methyl-[4- 3,4-Difluorophenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- sulfamoylchloride dihydro-2H-quinoline-1-quinolin-6-yloxy)- sulfonic acid (3,4-difluoro- but-2-enyl]-aminephenyl)-amide 14.20 6-[4-(Allyl-methyl-amino)- 496 Allyl-methyl-[4-4-Trifluoromethyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- phenyl-dihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfamoylchloride sulfonicacid (4- but-2-enyl]-amine trifluoromethyl-phenyl)- amide 14.216-[4-(Allyl-methyl-amino)- 446 Allyl-methyl-[4- 3-Fluorophenyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- sulfamoylchloridedihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonic acid (3-fluoro-but-2-enyl]-amine phenyl)-amide 14.22 6-[4-(Allyl-methyl-amino)- 453Allyl-methyl-[4- 4-Cyanophenyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-sulfamoylchloride dihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonicacid (4-cyano- but-2-enyl]-amine phenyl)-amide 14.236-[4-(Allyl-methyl-amino)- 464 Allyl-methyl-[4- 2,4-Difluorophenyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- sulfamoylchloridedihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonic acid (2,4-difluoro-but-2-enyl]-amine phenyl)-amide 14.24 6-[4-(Allyl-methyl-amino)- 458Allyl-methyl-[4- 4-Methoxyphenyl- but-2-enyloxy]-3,4-(1,2,3,4-tetrahydro- sulfamoylchloride dihydro-2H-quinoline-1-quinolin-6-yloxy)- sulfonic acid (4-methoxy- but-2-enyl]-aminephenyl)-amide 14.25 6-[4-(Allyl-methyl-amino)- 464 Allyl-methyl-[4-2,5-Difluorophenyl- but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro-sulfamoylchloride dihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonicacid (2,5-difluoro- but-2-enyl]-amine phenyl)-amide 14.266-[4-(Allyl-methyl-amino)- 428 Allyl-methyl-[4- Phenyl-but-2-enyloxy]-3,4- (1,2,3,4-tetrahydro- sulfamoylchloridedihydro-2H-quinoline-1- quinolin-6-yloxy)- sulfonic acid (phenyl)-but-2-enyl]-amine amide 14.27 6-[5-(Allyl-methyl-amino)- 478Allyl-methyl-[5- 4-Chlorophenyl- pentyloxy]-3,4-dihydro-2H- (1 Cl)(1,2,3,4-tetrahydro- sulfamoylchloride quinoline-1-sulfonic acidquinolin-6-yloxy)- (4-chloro-phenyl)-amide pentyl]-amine 14.286-[5-(Allyl-methyl-amino)- 522 Allyl-methyl-[5- 4-Bromophenyl-pentyloxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-bromo-phenyl)-amidepentyl]-amine 14.29 6-[5-(Allyl-methyl-amino)- 458 Allyl-methyl-[5-4-Methylphenyl- pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid p- quinolin-6-yloxy)-tolylamide acid pentyl]-amine 14.30 6-[5-(Allyl-methyl-amino)- 512Allyl-methyl-[5- 4-Trifluoromethyl- pentyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- phenyl- quinoline-1-sulfonic acidquinolin-6-yloxy)- sulfamoylchloride (4-trifluoromethyl-phenyl)-pentyl]-amine amide 14.31 6-[5-(Allyl-methyl-amino)- 469Allyl-methyl-[5- 4-Cyanophenyl- pentyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- sulfamoylchloride quinoline-1-sulfonic acidquinolin-6-yloxy)- (4-cyano-phenyl)-amide pentyl]-amine 14.326-[5-(Allyl-methyl-amino)- 474 Allyl-methyl-[5- 4-Methoxyphenyl-pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-methoxy-phenyl)-amidepentyl]-amine 14.33 6-[5-(Allyl-methyl-amino)- 462 Allyl-methyl-[5-4-Fluorophenyl- pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(4-fluoro-phenyl)-amide pentyl]-amine 14.34 6-[5-(Allyl-methyl-amino)-480 Allyl-methyl-[5- 3,4-Difluorophenyl- pentyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- sulfamoylchloride quinoline-1-sulfonic acidquinolin-6-yloxy)- (3,4-difluoro-phenyl)-amide pentyl]-amine 14.356-[5-(Allyl-methyl-amino)- 462 Allyl-methyl-[5- 3-Fluorophenyl-pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (3-fluoro-phenyl)-amidepentyl]-amine 14.36 6-[5-(Allyl-methyl-amino)- 480 Allyl-methyl-[5-2,4-Difluorophenyl- pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(2,4-difluoro-phenyl)-amide pentyl]-amine 14.376-[5-(Allyl-methyl-amino)- 480 Allyl-methyl-[5- 2,5-Difluorophenyl-pentyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (2,5-difluoro-phenyl)-amidepentyl]-amine 14.38 6-[6-(Allyl-methyl-amino)- 483 Allyl-methyl-[6-4-Cyanophenyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(4-cyano-phenyl)-amide hexyl]-amine 14.39 6-[6-(Allyl-methyl-amino)- 488Allyl-methyl-[6- 4-Methoxyphenyl- hexyloxy]-3,4-dihydro-2H-(1,2,3,4-tetrahydro- sulfamoylchloride quinoline-1-sulfonic acidquinolin-6-yloxy)- (4-methoxy-phenyl)-amide hexyl]-amine 14.406-[6-(Allyl-methyl-amino)- 492 Allyl-methyl-[6- 4-Chlorophenyl-hexyloxy]-3,4-dihydro-2H- (1 Cl) (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-chloro-phenyl)-amidehexyl]-amine 14.41 6-[6-(Allyl-methyl-amino)- 494 Allyl-methyl-[6-2,5-Difluorophenyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(2,5-difluoro-phenyl)-amide hexyl]-amine 14.426-[6-(Allyl-methyl-amino)- 536 Allyl-methyl-[6- 4-Bromophenyl-hexyloxy]-3,4-dihydro-2H- (1 Br) (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-bromo-phenyl)-amidehexyl]-amine 14.43 6-[6-(Allyl-methyl-amino)- 494 Allyl-methyl-[6-2,4-Difluorophenyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(2,4-difluoro-phenyl)-amide hexyl]-amine 14.446-[6-(Allyl-methyl-amino)- 472 Allyl-methyl-[6- p-Tolyl-hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid p- quinolin-6-yloxy)- tolylamide hexyl]-amine14.45 6-[6-(Allyl-methyl-amino)- 438 Allyl-methyl-[6- Butyl-hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- butylamide hexyl]-amine14.46 6-[6-(Allyl-methyl-amino)- 476 Allyl-methyl-[6- 3-Fluorophenyl-hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (3-fluoro-phenyl)-amidehexyl]-amine 14.47 6-[6-(Allyl-methyl-amino)- 458 Allyl-methyl-[6-Phenyl- hexyloxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- phenylamide hexyl]-amine14.48 6-[4-(Allyl-methyl-amino)- 430 Allyl-methyl-[4- Phenyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- phenylamide butyl]-amine14.49 6-[4-(Allyl-methyl-amino)- 464 Allyl-methyl-[4- 4-Chlorophenyl-butoxy]-3,4-dihydro-2H- (1 Cl) (1,2,3,4-tetrahydro- sulfamoylchloridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-chloro-phenyl)-amidebutyl]-amine 14.50 6-[4-(Allyl-methyl-amino)- 466 Allyl-methyl-[4-2,4-Difluorophenyl- butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro-sulfamoylchloride quinoline-1-sulfonic acid quinolin-6-yloxy)-(2,4-difluoro-phenyl)-amide butyl]-amine 14.516-[4-(Allyl-methyl-amino)- 448 Allyl-methyl-[4- 4-Fluorophenyl-butoxy]-3,4-dihydro-2H- (1,2,3,4-tetrahydro- sulfonamylchoridequinoline-1-sulfonic acid quinolin-6-yloxy)- (4-fluoro-phenyl)-amidebutyl]-amine

Example 15

Sulfamoyl chlorides were prepared according to the following procedure.3 equivalents of the corresponding amine were dissolved in CH₂Cl₂ (1ml/mmol) and placed in an ice bath. A solution of chlorosulfonic acid (1eq.) in CH₂Cl₂ (0.5 ml/mmol) was added slowly (30 min). The reactionmixture was stirred at 0° C. for a further 30 min. Afterwards, the icebath was removed and the stirring was continued for 1 h at roomtemperature. The precipitate was collected by filtration and dried underhigh vacuum. This salt was suspended in toluene (1 ml/mmol amine) andPCl₅ (1 eq) was added. The mixture was stirred at 75° C. for 2 h, cooledto room temperature and filtered. The solid residue was washed withtoluene. The filtrate was evaporated and dried under high vacuum. Theresulting crude sulfamoyl chloride was used in the next step withoutfurther purification. The following sulfamoyl chlorides were preparedfrom the corresponding amines: Phenylsulfamoyl chloride,2,4-Difluoro-phenylsulfamoyl chloride, 2,5-Difluoro-phenylsulfamoylchloride, 3,4-Difluoro-phenylsulfamoyl chloride, 3-Fluorophenyl-sulfamoyl chloride, 4-Fluoro-phenylsulfamoyl chloride,4-Chloro-phenylsulfamoyl chloride, 4-Bromo-phenylsulfamoyl chloride,4-Methyl-phenylsulfamoyl chloride, 4-trifluoromethyl-phenylsulfamoylchloride, 4-Cyano-phenylsulfamoyl chloride, 4-Methoxy-phenylsulfamoylchloride, Butylsulfamoyl chloride.

Example 16

16.1

To 33.3 g (0.3 mol) 3-fluoroaniline in 160 ml CH₂Cl₂ were added 450 mlof a 0.7 M aqueous NaHCO₃-solution. The resulting mixture was treateddropwise with 34.6 ml (0.41 mol) methylchloroformate within a period of20 min. After stirring overnight the layers were separated and theorganic layer was washed with saturated aqueous NaCl and dried withMgSO₄. After evaporation of ca. 60% of the solvent, 600 ml of hexanewere added, whereby (3-Fluoro-phenyl)-carbamic acid methyl esterprecipitated as a colorless solid that was filtered off and dried i.v.(41 g (81%)).

The solid was dissolved in 600 ml acetonitrile and treated subsequentlywith 50 g (0.28 mmol) N-bromosuccinimide and 2.13 ml (0.024 mol)trifluormethane sulfonic acid. After stirring at room temperature during12 hours, ca. 50% of the solvent were evaporated, the resulting mixturediluted with 1000 ml EtOAc, and washed subsequently with saturatedaqueous NaHCO₃ and saturated aqueous NaCl. Drying of the combinedorganic layers with MgSO₄, evaporation of the solvent, and columnchromatography of the residue on silica gel with hexane/EtOAc 8:1 andthen 2:1 gave 39 g (64%) (4-Bromo-3-fluoro-phenyl)-carbamic acid methylester as a colorless solid. The solid was dissolved in 390 mlacetonitrile, treated subsequently with 39 g (0.172 mol)N-iodosuccinimide and 1.4 ml (0.016 mol) trifluormethanesulfonic acid at0° C. and left to stirr at room temperature during 10 hours. Cooling thereaction mixture to 0° C. led to precipitation of(4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester as colorlesscrystals that were filtered off and dried (26.7 g, 44%). Dilution of thefiltrate with 600 ml hexane followed by subsequent washing withsaturated aqueous NaHCO₃ and 0.5M aqueous NaS₂O₃, drying of the organiclayer with MgSO₄, evaporation of the solvent, and recrystallization ofthe residue in acetonitrile gave an additional 6.3 g (12%) of(4-Bromo-5-fluoro-2-iodo-phenyl)-carbamic acid methyl ester (total: 33g, 56%), MS: 373 (M, 1Br).

16.2

A mixture of 70 mg (0.1 mmol) Pd(PPh₃)₂C1₂ and 27 mg (0.142 mmol) CuI intriethylamine was refluxed under argon during 20 min, cooled to 0° C.,treated with 7 g (0.019 mmol) (4-Bromo-5-fluoro-2-iodo-phenyl)-carbamicacid methyl ester, stirred 10 min at room temperature, treated with 2.95(0.021 mmol) ethinyltrimethylsilane, and stirred 1 h at roomtemperature. 2M aqueous HCl and ice were added and the mixture extractedthree times with EtOAc. The combined organic layers were washedsubsequently with H₂O and saturated aqueous NaCl, dried with MgSO₄ andthe solvent was evaporated. The crude product obtained was dissolved in50 ml tert-butanol, treated with 3.2 g (0.023 mol) KOH and the resultingmixture refluxed for 1.5 h. The solvent was evaporated and the residuedistributed between icy water and Et₂O. The organic layer was washedwith water and dried with MgSO₄. Evaporation of the solvent and columnchromatography on silica gel with hexane/EtOAc 9:1 gave of 3.2 g (80%)5-Bromo-6-fluoro-1H-indole, MS: 213 (M, 1Br).

16.3

To a solution of 2.1 g (9.81 mmol) 5-Bromo-6-fluoro-indole in 35 ml ofDMF were added 1.54 g (13.76 mmol) KOtBu and 3.0 g (13.76 mmol)Di-tert.butylcarbonate, and the solution was stirred for 1 hr at roomtemperature and 30 min at 60° C. The mixture was poured into water,acidified with 2M aqueous HCl and extracted with Et₂O. Drying of theorganic layers with MgSO₄, evaporation of the solvent, andchromatography on silica gel with hexane/EtOAc 49:1 gave 2.6 g (84%)5-Bromo-6-fluoro-indole-1-carboxylic acid tert-butyl ester as acolorless liquid, MS: 313 (M, 1Br).

16.4

A mixture of 3.04 g (9.67 mmol) 5-Bromo-6-fluoro-indole-1-carboxylicacid tert-butyl ester, 670 mg (0.58 mmol) Pd(PPh₃)₄, and 111 mg (0.58mmol) CuI in 25 ml of piperidine was heated to 60° C., treated with 1.61ml (1.80 mmol) 4-pentyne-1-ol and stirred at 80° C. for 2 hrs. Aftercooling to room temperature the mixture was poured into water, acidifiedwith 2M aqueous HCl and extracted with EtOAc. Drying of the combinedorganic layers with MgSO₄, evaporation of the solvent, andchromatography on silica gel with CH₂Cl₂ gave 2.6 g (85%) of6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butylester as a viscous orange oil, MS: 318 (MH⁺).

16.5

A solution of 950 mg (0.3 mmol)6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-indole-1-carboxylic acid tert-butylester in 20 ml EtOH was treated with 2 ml of saturated aqeous NaOH andstirred during 2 hours at 60° C. 75% of the solvent were evaporated, theresulting mixture was poured into 5 ml of water, acidified with 2Maqueous HCl, and extracted with EtOAc. Drying of the combined organiclayers with MgSO₄, evaporation of the solvent, and chromatography onsilica gel with CH₂Cl₂ gave 550 mg (84%) of5-(6-Fluoro-1H-indol-5-yl)-pent-4-yn-1-ol as a viscous light yellow oil,MS: 218 (M).

16.6

A solution of 109 mg (0.5 mmol)5-(6-Fluoro-1H-indol-5-yl)-pent-4-yn-1-ol in 3 ml AcOH/TFA 2:1 wascooled to 0° C., treated with NaCNBH₃ and stirred for 1 hour at roomtemperature. The mixture was poured into icy water, made stronglyalkaline by the addition of 2M NaOH, and extracted with EtOAc. Drying ofthe combined organic layers with MgSO₄, evaporation of the solvent, andchromatography on silica gel with CH₂Cl₂/MeOH 49:1 gave 80 mg (73%) of5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol as a colorlessoil, MS: 220 (MH⁺).

16.7

A solution of 99 mg (0.45 mmol)5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol and 0.155 ml (0.90mmol) N-Ethyldiisopropylamine in 2 ml CH₂Cl₂ was treated with 0.125 ml(0.90 mmol) 4-chlorophenyl chloroformate and stirred at room temperatureduring 1 hour. The mixture was poured into water, extracted with EtOAcand the combined organic layers were dried with MgSO₄. Evaporation ofthe solvent, chromatography on silica gel with CH₂Cl₂/MeOH 49:1 gave 125mg (74%) of6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid4-chloro-phenyl ester as a viscous light yellow oil, MS: 374 (MH⁺, 1Cl).

16.8

In analogy to example 16.7,5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol andtoluene-4-sulfonylchloride gave5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-ol,MS: 374 (MH⁺, 1Cl).

16.9

A solution of 120 mg (0.321 mmol)6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid4-chloro-phenyl ester and 0.164 ml (0.96 mmol) N-ethyldiisopropylaminein 2 ml CH₂Cl₂ was treated with 0.03 ml (0.385 mmol) of methanesulfonylchloride and stirred at room temperature for 1 hour. The mixture waspoured into Et₂O and washed with 0.5 M HCl. Drying of the organic layerwith MgSO₄, evaporation of the solvent, and chromatography on silica gelwith CH₂Cl₂ gave 91 mg (61%) of6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester as a colorless oil, MS: 452 (MH⁺, 1Cl).

16.10

A solution of 30 mg (0.066 mmol) of6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester and 0.1 ml (0.10 mmol) N-methylallylamine in0.5 ml of DMF was stirred at 80° C. for 2 hours. The mixture was pouredinto 0.5 M aqueous NaOH and extracted with EtOAc. Drying of the combinedorganic layers with MgSO₄, evaporation of the solvent, andchromatography on silica gel with EtOAc/MeOH/NEt₃ 10:1:0.1 gave 19 mg(67%) of5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester as a light brown oil, MS: 427 (MH⁺, 1Cl).

16.11

In analogy to example 16.10,6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester and 2-(methylamino)ethanol were converted toyield6-Fluoro-5-{5-[(2-hydroxy-ethyl)-methyl-amino]-pent-1-ynyl}-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester as a colorless oil, MS: 430 (M, 1Cl).

16.12

In analogy to example 16.11,6-Fluoro-5-(5-methanesulfonyloxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester and 2(ethylamino)ethanol were converted toyield5-{5-[Ethyl-(2-hydroxy-ethyl)-amino]-pent-1-ynyl}-6-fluoro-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester as a colorless oil, MS: 445 (MH⁺, 1 Cl).

16.13

A solution of 50 mg (0.141 mmol) of5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-oland 0.072 ml (0.42 mmol) diisopropyl ethylamine in 2 ml CH₂Cl₂ wastreated at 0° C. with 0.033 ml (0.42 mmol) methanesulfonylchloride andstirred at room temperature for one hour. Addition of aqueous 0.1 M HCl,extraction with Et₂O, drying of the organic layer with MgSO₄, andevaporation of the solvent gave 60 mg of Methanesulfonic acid5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynylester as brown oil of which 12 mg were dissolved in 0.5 ml DMF, treatedwith 0.043 ml (0.053 mmol) 2-(methylamino)ethanol and stirred at 80° C.during 2 hours. Evaporation of the solvent and excess2-(methylamino)ethanol and chromatography on silica gel withEtOAc/MeOH/NEt₃ 10:1:0.1 gave 10 mg (82%) of2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanolas a light yellow oil, MS: 431 (MH⁺).

16.14

In analogy to example 16.13,5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-yn-1-oland 2-(ethylamino)ethanol instead of 2-(methylamino)ethanol wereconverted to yield2-(Ethyl-{5-[6-fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-amino)-ethanolas a light yellow oil, MS: 445 (MH⁺).

Example 17

17.1

Hydrogenolysis at atmospheric pressure of 5 mg (0.013 mmol)5-[5-(Allyl-methyl-amino)-pent-1-ynyl]-6-fluoro-2,3-dihydro-indole-1-carboxylicacid 4-chloro-phenyl ester in 0.5 ml AcOH in the presence of 5 mg 10%Pd/C during 12 hrs, followed by filtration, evaporation of the AcOH,distribution of the residue between Et₂O and 0.5 M NaOH, drying of theorganic layer with Na₂SO₄, evaporation of the solvent and chromatograpyon silica gel with EtOAc/MeOH/NEt₃ 10:1:0.1 gave 3 mg (64%) of6-Fluoro-5-[5-(methyl-propyl-amino)-pentyl]-2,3-dihydro-indole-1-carboxylicacid phenyl ester as a yellow oil, MS: 399 (MH⁺)

17.2

In analogy to example 17.1, hydrogenolysis of2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pent-4-ynyl}-methyl-amino)-ethanolyielded2-({5-[6-Fluoro-1-(toluene-4-sulfonyl)-2,3-dihydro-1H-indol-5-yl]-pentyl}-methyl-amino)-ethanol.MS: 435 (MH⁺).

Example A

Tablets containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per tablet Compound of formula I 10.0–100.0 mg Lactose 125.0mg Maize starch 75.0 mg Talc 4.0 mg Magnesium stearate 1.0 mg

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mgMaize starch 20.0 mg Talc 5.0 mg

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Water forinjection solutions ad 1.0 ml

1. A compound selected from the group consisting of: compounds offormula (I)

wherein U is O or a lone pair, V is a) O, S, NR¹, or CH₂, and L islower-alkylene or lower-alkenylene, b) —CH═CH— or —C≡C—, and L islower-alkylene or a single bond, W is CO, COO, CONR², CSO, CSNR², SO₂,or SO₂NR², X is hydrogen or one or more optional halogen and/orlower-alkyl substituents, m is 2, n is 0 to 7, A¹ is hydrogen,lower-alkenyl, or lower-alkyl optionally substituted by hydroxy,lower-alkoxy, or thio-lower-alkoxy, A² is cycloalkyl,cycloalkyl-lower-alkyl, lower-alkenyl, lower-alkinyl, or lower-alkyloptionally substituted by hydroxy, lower-alkoxy or thio-lower-alkoxy, A³and A⁴ independently from each other are hydrogen or lower-alkyl, or A¹and A² or A¹ and A³ are bonded to each other to form a ring and -A¹-A²-or -A¹-A³- are lower-alkylene or lower-alkenylene, optionallysubstituted by R³, in which one —CH₂— group of -A¹-A²- or -A¹-A³- canoptionally be replaced by NR⁴, S, or O, A⁵ is cycloalkyl,cycloalkyl-lower-alkyl, heterocycloalkyl-lower-alkyl, aryl,aryl-lower-alkyl, heteroaryl, heteroaryl-lower-alkyl, lower-alkyloptionally substituted with hydroxy or lower-alkoxy, alkenyl optionallysubstituted with hydroxy, or alkadienyl optionally substituted withhydroxy, R³ is hydroxy, lower-alkoxy, thio-lower-alkoxy, N(R⁵,R⁶), orlower-alkyl optionally substituted by hydroxy, R¹, R², R⁴, R⁵, and R⁶independently from each other are hydrogen or lower-alkyl;pharmaceutically acceptable salts of compounds of formula (I); andpharmaceutically acceptable esters of compounds of formula (I).
 2. Thecompound according to claim 1, wherein U is a lone pair.
 3. The compoundaccording to claim 2, wherein V is O or CH₂, and L is lower-alkylene orlower-alkenylene.
 4. The compound according to claim 2, wherein V is—C≡C— and L is lower-alkylene or a single bond.
 5. The compoundaccording to claim 3, wherein n is
 0. 6. The compound according to claim3, wherein A¹ is lower-alkyl.
 7. The compound according to claim 6,wherein A¹ is methyl or ethyl.
 8. The compound according to claim 3,wherein A² is lower-alkenyl, or lower-alkyl optionally substituted byhydroxy or lower-alkoxy.
 9. The compound according to claim 8, whereinA² is 2-propenyl or 2-hydroxy-ethyl.
 10. The compound according to claim3, wherein A¹ and A² are bonded to each other to form a ring and -A¹-A²-is lower-alkylene or lower-alkenylene, optionally substituted by R³, inwhich one —CH₂— group of -A¹-A²- can optionally be replaced by NR⁴, S,or O, wherein R³ and R⁴ are as defined in claim
 1. 11. The compoundaccording to claim 3, wherein A³ is hydrogen.
 12. The compound accordingto claim 11, wherein A⁴ is hydrogen.
 13. The compound according to claim3, wherein A⁵ is cycloalkyl, cycloalkyl-lower-alkyl,heterocycloalkyl-lower-alkyl, aryl, aryl-lower-alkyl, heteroaryl,heteroaryl-lower-alkyl, or lower-alkyl optionally substituted withhydroxy or lower-alkoxy.
 14. The compound according to claim 13, whereinA⁵ is phenyl or benzyl, optionally substituted by 1 to 3 substituentsindependently selected from the group consisting of fluorine andchlorine, or wherein A⁵ is lower-alkyl.
 15. The compound according toclaim 14, wherein A⁵ is phenyl, 4-fluoro-phenyl, 4-chloro-phenyl, butyl,or pentyl.
 16. The compound according to claim 3, wherein W is COO,CONR², CSO, or CSNR², and R² is hydrogen.
 17. The compound according toclaim 3, wherein X is hydrogen.
 18. The compound according to claim 3,wherein X is fluorine.
 19. A compound selected from the group consistingof compounds of formula (VII)

wherein V is O or CH₂; L is lower-alkylene or lower-alkenylene; W isCOO, CONH, CSNH or CSO; A¹ is hydrogen or lower-alkyl; A² is lower alkylor lower alkenyl; m is 2; and A⁵ is lower alkyl, phenyl or lower alkylphenyl, wherein the phenyl group is optionally substituted with halogen;pharmaceutically acceptable salts of compounds of formula (VII); andpharmaceutically acceptable esters of compound of formula (VII).
 20. Thecompound according to claim 19, wherein V is CH₂.
 21. The compoundaccording to claim 19, wherein V is O.
 22. The compound according toclaim 21, wherein W is COO.
 23. The compound according to claim 21,wherein W is CONH.
 24. The compound according to claim 23, wherein thecompound of formula (VII) is6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid (4-fluoro-phenyl)-amide.
 25. The compound according to claim 24,which is6-[4-(Allyl-methyl-amino)-but-2-enyloxy]-3,4-dihydro-2H-quinoline-1-carboxylicacid (4-fluoro-phenyl)-amide.
 26. The compound according to claim 21,wherein W is CSNH.
 27. The compound according to claim 21, wherein W isCSO.
 28. A pharmaceutical composition comprising a compound according toclaim 1 and at least one of a pharmaceutically acceptable carrier orpharmaceutically acceptable adjuvant.